Metabolism Q and A

Hereditary hemochromatosis exhibits an autosomal recessive inheritance pattern.
The frequency
of the disease in the general population is 1%. A man who is a known heterozygous carrier
marries a woman from the general population. Assuming Hardy-Weinberg equilibrium in this
population, which of the following is the probability that he and his partner will produce a child
who has hemochromatosis?
 Incorrect Answer Image A.0.025
This answer assumes that the mother has a 5% chance of passing the disease allele to her
child, which is incorrect. The mother has a 10% chance of passing the defective allele to
her child.
[24.3% chose this answer.]
 Correct Answer Image B.0.05
The probability of the couple having a child with hemochromatosis is 0.05 (1 in 20). The
man has a 50% chance of transmitting the mutated allele, and the woman has a 10%
chance of transmitting the mutated allele (since the disease allele frequency in the
population is 10%).
[39.1% correctly chose this answer.]
 Incorrect Answer Image C.0.09
This answer is incorrect. The probability of the couple having a child with
hemochromatosis is 0.05.
 Incorrect Answer Image D.0.10Incorrect Answer Image
0.10 represents the disease allele frequency in the general population, not the chance that
the child of the couple described in the vignette will have hemochromatosis.
 Incorrect Answer Image E.0.25
0.25 is the probability that a child of two known carriers of an autosomal recessive
disorder would have a child with the disorder.
ReKap
Hardy-Weinberg equilibrium formula: p2 + 2pq +q2 = 1.
 p = frequency of allele 1 (normal allele).

 q = frequency of allele 2 (disease-producing allele).
 p2 = frequency of genotype 1-1 (homozygous normal).
 2pq = frequency of genotype 1-2 (heterozygous carrier).
 q2 = frequency of genotype 2-2 (homozygous affected).
Analysis
The correct answer is B. One must first determine the probability that the man's
partner will also be a heterozygous carrier. This is done by applying the Hardy-
Weinberg equilibrium (HWE) rule (p2 + 2pq +q2 = 1), where

 p2 is the frequency of homozygous normal individuals
 2pq is the frequency of heterozygous individuals (carriers)
 q2 is the frequency of homozygous affected individuals
If the frequency of affected homozygotes is 1% (q 2), then the gene frequency (q) of the
hemochromatosis mutation is the square root of 1%, or 0.10 (q 2 = 0.01, so q = √0.01
and then q = 0.1 and p = 0.9, since p + q = 1). Then, the estimated frequency of
heterozygous carriers in the population, 2pq, is 2 × 0.9 × 0.1 = 0.18 (notice that we do
not use the 2q approximation in this case because p is not approximately equal to 1).
The probability that two heterozygous carriers will produce an affected offspring is 0.25
(25%), so the probability that the man mates with a carrier and the probability that they
will, in turn, produce an affected offspring is obtained by multiplying the two probabilities
together: 0.25 × 0.18 = 0.045. Additionally, there is a small chance (0.01) that the
person he mates with will be a homozygote, and thus there is a chance (0.01/2) that the
offspring of this mating will be affected, since the man has a 1 in 2 chance of
transmitting the hemochromatosis gene. The correct answer, then, is 0.045 + 0.005 =
0.05.
Exam tip: When faced with this type of problem on the exam, it is not necessary to
perform all of the preceding calculations. Instead of considering all of the possible
matings, focus on the gametes in the population as a whole. We know that the man
is heterozygous for the trait. We know that there is a 50% (0.5) chance that one of
his sperm carrying an "h" (a mutated allele) will fertilize the egg. We know that if
the population is in HWE, the frequency of eggs that carry h is equal to the allele
frequency q, or 0.1. So the chance that he will have a child with hemochromatosis
is (0.5) x (0.1) = (0.05).

A 7-year-old girl is taken to a pediatrician because of recent fatigue. Her sister and older brother have
been diagnosed with hemolytic anemia and she has two younger brothers that are asymptomatic. The
patient's mother and father are second cousins, and neither expresses the symptoms of this disorder.
Physical examination reveals mild facial pallor and scleral icterus. There is mild splenomegaly
ReKap
 Consanguinity increases the incidence of any autosomal recessive condition.

 Pyruvate kinase (PK) deficiency is a primary hemolytic anemia inherited as an autosomal
recessive trait; therefore, both sexes are equally affected.
 In severe forms, PK deficiency is 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.
Analysis
The 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 patient's presentation is that
the disorder appears to be hereditary and that it is not X-linked, because there is no
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 of glucose 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 unable to produce sufficient ATP to maintain
normal plasma membrane Na+–K+ ATPase activity, 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 2,3-
bisphosphoglycerate (2,3-BPG) in red cells are present, leading to a lower affinity of
hemoglobin for O2. Patients can present with fatigue, pallor, scleral icterus or general
jaundice, and splenomegaly (extravascular hemolysis). Echinocytes would be observed
on the peripheral blood smear.
Debranching enzyme (α-1,4, α-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 X-linked gene and hemolytic anemia in the woman's 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.
A 3-month-old girl is brought to the emergency department by her parents because of the onset
of seizures. Her parents say that the seizures occur several hours after each feeding. Her mother
also reports that she did not have any prenatal care. Physical examination of the infant shows
growth retardation and a demonstrably palpable liver. Laboratory studies show elevated lactate
and lipidemia in addition to a glucose level of 45 mg/dL. A defect involving which of the
following enzymes is most likely responsible for this patient's condition?
ReKap
 Glucose 6-phosphatase deficiency (Von Gierke disease) is an autosomal recessive

disorder.
 It is characterized by profound fasting hypoglycemia, lactic acidosis, hyperuricemia,
hyperlipidemia, and hepatomegaly due to both glycogen and fat accumulation.
Analysis
The correct answer is C. The demonstrably palpable liver indicates that the infant has
pronounced hepatomegaly. Hepatomegaly and hypoglycemic seizures strongly
suggest a glycogen storage disease (GSD).
Three of the enzymes listed are related to glycogen storage diseases:
 Acid maltase (choice A; also called lysosomal α1,4-glucosidase; deficiency results in

Pompe disease)
 Glucose-6-phosphatase (choice C; deficiency produces von Gierke disease, from which
this patient is suffering)
 Muscle phosphorylase (choice E; deficiency produces McArdle disease)
Von Gierke disease is a glycogen storage disease caused by a deficiency of
glucose-6-phosphatase (GSD type Ia) or of glucose-6-phosphate translocase (GSD
type Ib). It typically presents between 3-4 months of age with hypoglycemia,
hyperlipidemia, and lactic acidosis. Failure to thrive is also common in early life;
seizures may occur during episodes of profound hypoglycemia. The glycogen
accumulation in von Gierke disease occurs primarily in the liver and kidneys,
accounting for the enlargement of these organs. Gout may develop later because of the
derangement of glucose metabolism. Due to allelic heterogeneity, the onset of
symptoms may be delayed and, in some cases, symptoms may be milder. Von Gierke
disease, like most enzyme deficiencies, is inherited as an autosomal recessive
disorder.
Pompe disease (choice A) is a muscle glycogenolysis disorder associated with skeletal
and cardiac muscle involvement. The primary symptom in Pompe disease is severe
cardiomegaly. McArdle disease (choice E) is also a muscle glycogenolysis
manifesting with relatively mild symptoms (muscle cramps and weakness on
exercise, myoglobinuria). It causes muscle weakness beginning in the second or third
decade of life and no hepatomegaly, so this option can be excluded.
Beta-glucocerebrosidase deficiency (choice B) causes Gaucher disease, a lysosomal
storage disease, which is characterized by hepatosplenomegaly and glucocerebroside
accumulation in phagocytic cells.
Hexosaminidase A (choice D) deficiency is associated with Tay-Sachs disease, a
lysosomal storage disease, which is characterized by progressive neurologic
deterioration. Cherry-red spots in the macular region precede blindness. Note that
cherry-red spots are not pathognomonic for Tay-Sachs disease. They may also occur in
Niemann-Pick disease.
The table below summarizes the glycogen storage diseases.
Type Deficient Cardinal Clinical Glycogen

Enzyme Features Structure
I: von Gierke Glucose-6- Severe hypoglycemia, Normal
phosphatase lactic acidosis,
hepatomegaly,
hyperlipidemia,
hyperuricemia, short
stature doll-like facies,
protruding abdomen,
emaciated extremities
Type Deficient Cardinal Clinical Glycogen
Enzyme Features Structure
II: Pompe Lysosomal α1,4- Cardiomegaly, muscle Glycogen-
glucosidase weakness, death by 2 like material
years in inclusion
bodies
III: Cori Glycogen Mild hypoglycemia, Short outer
debranching liver enlargement branches
enzyme Single
glucose
residue at
outer branch
IV: Andersen Branching Infantile hypotonia, Very few
(amylopectinosis) enzyme cirrhosis, death by 2 branches,
years especially
toward
periphery
V: McArdle Muscle glycogen Muscle cramps and Normal
phosphorylase weakness on exercise,
myoglobinuria
VI: Hers Hepatic glycogen Mild fasting Norma
phosphorylase hypoglycemia,
hepatomegaly,
cirrhosis
A 42-year-old primigravid woman comes to the physician for a follow-up visit to receive the
results of an amniocentesis. The physician explains that her child has a chromosomal
abnormality that will likely result in intellectual disabilities and an increased risk for several
other conditions including congenital heart defects and acute lymphoblastic leukemia. Her child
most likely has which of the following chromosomal abnormalities?

Aside from intellectual disability, trisomy 21 is associated with numerous other medical
issues.
 Examples include acute lymphoblastic leukemia, cardiac malformations, Alzheimer-like
changes, epilepsy, duodenal atresia, and visual problems.
Analysis
The correct answer is C. In addition to the well-known intellectual disabilities
associated with Down syndrome (trisomy 21), affected individuals have an increased
incidence of a variety of medical problems. Acute myeloblastic leukemia (AML) is
seen in newborns and acute lymphoblastic leukemia (ALL) is seen in older
children.
In addition, congenital cardiac malformations are common (40–50% of cases), and
include atrial and ventricular septal defects, tetralogy of Fallot, and patent ductus
arteriosus. The development of the hypopharynx is often poor, predisposing to both
aspiration pneumonia and obstruction by enlarged adenoids. Nearly all boys are
infertile; girls are subfertile but can become pregnant. Epilepsy affects up to 10% of
children with Down syndrome. On occasion, the malformed head and neck region can
undergo atlantoaxial dislocation, causing a sudden or progressive quadriparesis. Other
malformations that occur with lower frequency include duodenal atresia and imperforate
anus. Acquired autoimmune hypothyroidism is frequent. Alzheimer-like changes
develop in mid-adulthood. Visual problems related to strabismus, nystagmus, or myopia
are common.
Trisomy 13 (choice A) and trisomy 18 (choice B) arise from nondisjunction of
an autosome, resulting in an individual in which all cells have three copies of 13 or 18,
respectively, instead of the normal two copies. Both conditions are associated with
severe intellectual disabilities and congenital heart defects. Both of these conditions are
usually fatal early in life.
 Trisomy 13, also known as Patau syndrome, have "rocker-bottom" feet, cleft lip and
palate, and polydactyly (extra fingers or toes), and cardiac and renal defects.
 Trisomy 18, also known as Edwards syndrome, is characterized by "rocker-bottom
feet", low birth weight, low set ears, micrognathia (small lower jaw), and clenched fists
with overlapping fingers, and congenital heart defects.
Although heart defects are common with both trisomy 13 and 18, neither is associated
with an increased risk of ALL.
Genotypes 45,XO (choice D) and 47,XXY (choice E) arise from nondisjunction of the
sex chromosomes, resulting in either the absence of one X chromosome (45,XO) or the
presence of an additional X chromosome (47,XXY). An individual with a 45,XO
genotype has Turner syndrome, whereas an individual with 47,XXY has Klinefelter
syndrome.
 Individuals with Turner syndrome are female, but the loss of the second X chromosome
affects several aspects of development both before and after birth. Common features of
Turner syndrome include short stature, webbed neck, lymphedema in the hands and feet,
skeletal abnormalities, and congenital heart defects. In addition, they have nonfunctional
ovaries, due to ovarian tissue degeneration before birth, and are infertile.
 Individuals with Klinefelter syndrome are male, but their sexual development is
impaired. They typically have small testes that are not able to produce sufficient amounts
of testosterone, resulting in delayed or incomplete puberty, gynecomastia, undescended
testes, micropenis, and infertility. As adults, they tend to be taller than their peers.
Neither Turner syndrome nor Klinefelter syndrome are associated with an increased risk
of ALL.
Hereditary hemochromatosis exhibits an autosomal recessive inheritance pattern. The frequency
of the disease in the general population is 1%. A man who is a known heterozygous carrier
marries a woman from the general population. Assuming Hardy-Weinberg equilibrium in this
population, which of the following is the probability that he and his partner will produce a child
who has hemochromatosis?
ReKap
Hardy-Weinberg equilibrium formula: p2 + 2pq +q2 = 1.
p = frequency of allele 1 (normal allele).

q = frequency of allele 2 (disease-producing allele).
p2 = frequency of genotype 1-1 (homozygous normal).
2pq = frequency of genotype 1-2 (heterozygous carrier).
q2 = frequency of genotype 2-2 (homozygous affected).
Analysis
The correct answer is B. One must first determine the probability that the man's
partner will also be a heterozygous carrier. This is done by applying the Hardy-
Weinberg equilibrium (HWE) rule (p2 + 2pq +q2 = 1), where
 p2 is the frequency of homozygous normal individuals

 2pq is the frequency of heterozygous individuals (carriers)
 q2 is the frequency of homozygous affected individuals
If the frequency of affected homozygotes is 1% (q 2), then the gene frequency (q) of the
hemochromatosis mutation is the square root of 1%, or 0.10 (q 2 = 0.01, so q = √0.01
and then q = 0.1 and p = 0.9, since p + q = 1). Then, the estimated frequency of
heterozygous carriers in the population, 2pq, is 2 × 0.9 × 0.1 = 0.18 (notice that we do
not use the 2q approximation in this case because p is not approximately equal to 1).
The probability that two heterozygous carriers will produce an affected offspring is 0.25
(25%), so the probability that the man mates with a carrier and the probability that they
will, in turn, produce an affected offspring is obtained by multiplying the two probabilities
together: 0.25 × 0.18 = 0.045. Additionally, there is a small chance (0.01) that the
person he mates with will be a homozygote, and thus there is a chance (0.01/2) that the
offspring of this mating will be affected, since the man has a 1 in 2 chance of
transmitting the hemochromatosis gene. The correct answer, then, is 0.045 + 0.005 =
0.05.
Exam tip: When faced with this type of problem on the exam, it is not necessary to
perform all of the preceding calculations. Instead of considering all of the possible
matings, focus on the gametes in the population as a whole. We know that the man
is heterozygous for the trait. We know that there is a 50% (0.5) chance that one of
his sperm carrying an "h" (a mutated allele) will fertilize the egg. We know that if
the population is in HWE, the frequency of eggs that carry h is equal to the allele
frequency q, or 0.1. So the chance that he will have a child with hemochromatosis
is (0.5) x (0.1) = (0.05).
Updated on 05/25/21
A 37-year-old woman with a history of acute intermittent porphyria comes to the physician
because of acute gastroenteritis. She has severe abdominal pain, tachycardia, hypertension, and
proximal muscle weakness. Which of the following laboratory findings is most likely to be seen
during an episode of this illness?
ReKap
 Acute intermittent porphyria (AIP) results from a deficiency of the enzyme

porphobilinogen deaminase (PBGD).
 In AIP, patients excrete delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in
the urine during the acute attacks.
 Attacks are characterized by abdominal pain, tachycardia, and neurologic effects. Patients
are not photosensitive.
Analysis
The correct answer is E. Acute intermittent porphyria (AIP) is the common form
of acute porphyria. It is an autosomal dominant condition that results from a partial
deficiency of the enzyme porphobilinogen deaminase (PBGD), also known
as hydroxymethylbilane synthase, which catalyzes the reaction (see figure below).
Note: Cutaneous porphyria tarda is the most common type of porphyria overall and is
the most common form of chronic porphyria. Acute forms present with abrupt, episodic
attacks, whereas chronic forms have dermatologic manifestations.

he figure above clearly
highlights the enzyme deficiencies causing acute intermittent porphyria and porphyria
cutanea tarda. Pay attention to the incidence and symptoms of these diseases.
AIP is more commonly seen in women, but the penetrance of the disease is only
about 15%. Phenotypically affected individuals rarely have episodes before
puberty. PBGD is present in all tissues and red blood cells (RBCs). Most patients
with the deficiency are clinically normal except when affected by certain
environmental factors, drugs (especially agents such

as barbiturates and alcohol that induce cytochrome P450 enzymes), or changes in
nutritional or hormonal state.
When symptoms do occur (as in the present case), the urine in rare patients may turn a
port-wine color due to porphobilin, an oxidation product of PBG. This color change
may also be observed in patient urine that has been left to stand and oxidize, but this is
rarely done since urine in suspected patients is generally sent for chemical testing.
Symptoms typically include abdominal pain, tachycardia, and neurologic effects.
Patients are not photosensitive. Affected patients excrete delta-aminolevulinic
acid (ALA) and PBG and there is an increase in serum ALA and PBG.
The diagnosis can usually be made by showing a decrease in PBGD activity in
RBCs, therefore choice B is incorrect.
Increased erythrocyte Zn-protoporphyrin (choice A) results when the last step in heme
synthesis does not take place. The last step is catalyzed by ferrochelatase, which
inserts ferrous iron into protoporphyrin to form heme. The step might not occur due
to lead poisoning, ferrochelatase defect, or severe iron deficiency. In any of these
cases, zinc inserts into the protoporphyrin forming the fluorescent Zn-
protoporphyrin.
Increased serum porphyrins (choice C) is incorrect because there would be an inability
to synthesize sufficient amounts of porphyrins due to a partial defect in PBGD.
Urinary and fecal coproporphyrins are increased (choice D) in individuals
with hereditary coproporphyria (decreased activity of coproporphyrinogen oxidase).
Many individuals with the disorder remain asymptomatic. Attacks may be triggered by
chemicals (including many medications such as oral contraceptives) or situations (e.g.,

fasting) that boost heme synthesis. Coproporphyria manifests with signs and symptoms
that include abdominal pain, neuropathies, constipation, and skin changes (e.g.,
photosensitivity). A decrease in urinary coproporphyrins is found in uroporphyrinogen
decarboxylase deficiency and congenital erythropoietic porphyria (decreased activity
of uroporphyrinogen III synthase).

A 5-year old boy (III-1) of Turkish descent is brought to his physician because of yellowness in his eyes.
The patient's mother explains that this appeared after taking a long-term antibiotic that the physician
prescribed for his severe chest infection. The physician performs a detailed analysis of his family (shown
below in the pedigree) that includes relatives who the mother knows have become ill when given the
same antibiotic. Which of the following is the most likely diagnosis?
ReKap
Glucose-6-phosphate dehydrogenase (G6PD) deficiency:
 X-linked recessive disorders predominantly affect males because males are hemizygous
for the X chromosome.
 Affected males inherit the mutant allele from their mothers.
 Affected males pass the mutant allele to all daughters, who are carriers, but to none of
their sons.
 G6PD deficiency, hemophilia A, and Duchenne muscular dystrophy are examples of X-
linked recessive diseases that are commonly tested.
Analysis
The correct answer is A. The pedigree is most consistent with X-linked
recessive inheritance. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is
the only X-linked recessive disorder listed and is consistent with the clinical aspects
described in the patient. The yellowness of the eyes is jaundice resulting from the
administration of a long-term antibiotic that can cause hemolytic episodes.
The hallmark of X-linked recessive inheritance is an abundance of affected males and
an absence of affected females. Males are hemizygous for the X chromosome, so
the phenotype is expressed with only one copy of the defective gene. Females have two
copies of the X chromosome, so they appear phenotypically normal although they may
be a carrier for the recessive allele. Since males inherit their X chromosome from
their mother, she must carry the trait (or be affected by the disease). Affected males
cannot pass the disease to male offspring. Other X-linked recessive diseases
include Lesch-Nyhan disease, hemophilia A, and Duchenne muscular dystrophy.

Leber hereditary optic neuropathy (choice B) is a relatively common cause of acute or
subacute vision loss, especially in young men. It exhibits a mitochondrial inheritance
pattern. The hallmark of this pattern is matrilineal inheritance — the inheritance of
affected genes from the mother. All of the children of an affected woman will be affected
since they receive mitochondrial DNA from the female parent almost exclusively.
Affected males do not contribute mitochondria to progeny, so their children will not
receive the trait. The pedigree for a mitochondrial disorder would show an affected
mother with affected children. The affected female children will have affected progeny
while the affected male children will have normal progeny (assuming their mate is
unaffected).
Neurofibromatosis (choice C) shows an autosomal dominant inheritance pattern, so
the phenotype will be expressed if one mutant allele is present. Deleterious autosomal
dominants occur at very low frequencies, so affected individuals are almost always
heterozygous for the trait. Since the gene is located on an autosome, both male and
female progeny can be affected and affected persons are expected in every generation.
Other autosomal dominant diseases include Ehlers-Danlos syndrome, Huntington
disease, and osteogenesis imperfecta.
Sickle cell anemia (choice D) and Tay-Sachs disease (choice E) are both inherited in
an autosomal recessive manner. For the phenotype of the autosomal recessive to be
expressed, the recessive allele must be present in both alleles. Both male and female
children can be affected. The pedigree would be expected to show both males and
females equally affected and the tendency to skip generations. Consanguinity is
commonly see in families with autosomal recessive disease.

A 38-year-old obese man comes to the physician for a routine examination. He says that he has
been on a very strict, calorie-restricted diet that includes very small amounts of carbohydrates in
an effort to lose weight. Physical examination shows no abnormalities. Laboratory studies show
a low-normal level of blood glucose. Which of the following is the source of the majority of the
newly synthesized glucose in this patient?
ReKap
 During dieting by an obese person, 80% of glucose comes from fat breakdown, more
specifically from the glycerol backbone of triglycerides, which enters gluconeogenesis.
 During starvation, the major source of glucose after depletion of glycogen stores is also
from gluconeogenesis; 80% of glucose comes from amino acid degradation and 20% of
glucose comes from glycerol.
Analysis
The correct answer is D. Glycerol liberated from the breakdown of fats is the main
carbon source for gluconeogenesis in a dieting obese person. Specifically, glycerol
can be phosphorylated by glycerol kinase (which uses ATP) to form glycerol-3-
phosphate, which can, in turn, enter the gluconeogenic pathway via oxidation
to dihydroxyacetone phosphate. This pathway contributes about 80% of the glucose
in dieting obese individuals, and about 20% of the glucose (behind the amino acid
pathways) in truly starving individuals.
Many amino acids (choice A) are gluconeogenic, but these pathways are more
important in starvation than in dieting. The degradation of branched-chain amino acids
produces alanine that can be used to synthesize glucose.
Ethanol (choice B) is not gluconeogenic, but is produced in small amounts by gut
bacteria.
Fatty acids from fat (choice C) that undergo beta-oxidation produce acetyl-CoA,
which does not make glucose and is either oxidized to CO 2 or, in hepatocytes,
converted to acetoacetate and 3-hydroxybutyrate, which can be released and serve

as an energy source for nonhepatic tissues (skeletal and cardiac muscle, adrenal
cortex) and in true starvation, the brain). Beta-oxidation of fatty acids in hepatocytes
provides an important source of ATP and NADH to enable gluconeogenesis.
A very minor exception to the statement that fatty acids cannot be converted to glucose
are odd-numbered fatty acids. At the end of β-oxidation, they release 1 molecule
of propionyl-CoA. Propionyl-CoA can be converted in a 2-step pathway (the propionyl-
CoA pathway) to produce 1 molecule of succinyl-CoA, and then the extra succinyl-CoA
converted to one-half a molecule of glucose. In a quantitative sense, this contributes
very little glucose to the cell, but this point should be remembered for the USMLE.
Purine catabolism (choice E) produces the waste product uric acid, which is excreted in
urine.
A 26-month-old boy is brought to the physician by his parents because he has poor eye contact
and keeps flapping his hands and chewing on them. He has delayed social, motor, and language
skills. Physical examination shows a long narrow face, large ears, and flat feet. Which of the
following best explains the findings seen in the boy?
ReKap
 Fragile X syndrome is the most common inherited syndrome that leads to intellectual
disability.
 Fragile X syndrome is caused by the expansion of a CGG trinucleotide repeat, which
leads to methylation of the 5' promoter region which prevents the affected genes from
being expressed.
 Affected males have a wide range of behavioral and cognitive manifestations.
 Females tend to have fewer and milder abnormalities than males because they inherit two
X chromosomes, one of which is inactivated randomly in each cell, leaving them a
mosaic of normal and abnormal gene expression.
Analysis
The correct answer is A. The features described are typical of the familial form of
intellectual disability known as fragile X syndrome. This disorder is the most common
heritable cause of intellectual disability, impacting approximately 1:2,000 males. Striking
features of this disease are that the clinical features tend to worsen with each
successive generation and that males are usually much more severely affected than
females, although nearly 50% of females with the full mutation demonstrate
characteristic physical features and developmental delay.
The explanation apparently involves a region of DNA (FMR1 gene) on the X
chromosome that normally contains 6 to 54 tandem repeats of the sequence CGG.

Individual carriers of fragile X syndrome have a premutation that can contain up to 200
CGG repeats. Clinically affected individuals have full mutations with 200 to 4,000
repeats of the CGG sequence. The expansion leads to methylation of the 5' region,
an epigenetic change of gene expression, and gene silencing. Amplification of
premutations to full mutations of the FMR1 gene is much more likely to occur during
oogenesis than spermatogenesis. This is in contrast to another trinucleotide
disorder, Huntington disease, in which paternal amplification is more prominent.
Genomic imprinting (choice B) is a phenomenon in which the phenotypic expression of
a gene differs if the gene is inherited from the mother rather than the father. An example
of this effect is Angelman ("happy puppet") syndrome, caused by a deletion of band
q12 in the maternal copy of chromosome 15. The same deletion in paternal
chromosome 15 produces a different disease, called Prader-Willi syndrome.
Angelman syndrome is characterized by cognitive impairment, speech delay, ataxic
gait, and a happy demeanor. Prader-Willi syndrome is characterized by hyperphagia,
obesity, and hypogonadism.
A Robertsonian translocation (choice C) is a chromosomal rearrangement in which the
short arm of two acrocentric chromosomes are lost and the long arms combine to form
a derivative chromosome (see figure). The acrocentric chromosomes are 13, 14, 15, 21,
22, and Y. Because a Robertsonian translocation is found in 5% of individuals
with Down syndrome, karyotyping affected individuals is critical even when a diagnosis
can be made based on clinical findings because Robertsonian translocations can be
inherited from a carrier parent. If a translocation is identified, additional family members
should be karyotyped.
Trisomy 13 (Patau syndrome; choice D) is characterized by microcephaly, intellectual
disability, cleft lip and palate, polydactyly, and rocker-bottom feet. Survival is rare
beyond 1 year of age.
Trisomy 18 (Edwards syndrome; choice E) is characterized by intellectual disability,
micrognathia, low-set ears, cardiac defects, renal defects, and rocker-bottom feet.
Survival is rare beyond 1 year of age.

A 27-year-old man comes to the physician for a routine examination. He takes no medications
and has a family history of type 2 diabetes mellitus. He is not sexually active and does not smoke
cigarettes, drink alcohol, or use drugs. His diet primarily consists of fast food, as well as three
daily 16-oz bottles of a sugar-containing drink. This drink transiently raises his blood glucose
and triggers insulin release, which subsequently increases glucose absorption by skeletal muscle.
Which of the following glucose transporters (GLUT) is most likely principally involved in this
latter process?
ReKap
 GLUT4 is found in fat, skeletal muscle, and cardiac muscle; it mediates insulin-
stimulated glucose uptake.
 Insulin causes GLUT4-laden cytoplasmic vesicles to be inserted into the plasma
membrane, which facilitates glucose uptake.
Analysis
The correct answer is D. Glucose transporters (GLUTs) are a family of 14 Na+-
independent, facilitated glucose transporters with specific tissue
distributions. GLUT4 (SLC2A4 gene) in particular is found primarily in adipose
tissue and striated muscle (i.e., skeletal and cardiac). It facilitates insulin-
dependent glucose uptake, as insulin stimulates incorporation of GLUT4-laden vesicles
into the plasma membrane. Skeletal and cardiac muscle contraction increases GLUT4
expression independently of insulin.
GLUT4 expression on the plasma membrane is stimulated by the presence of insulin.
Increased insulin concentration leads to exocytosis of vesicles containing membrane-
bound GLUT4.
GLUT1 (SLC2A1; choice A) is found primarily in red blood cells, the blood-brain
barrier (e.g., cerebral capillary endothelium), and the kidney (proximal straight tubule).
In the brain, GLUT1 is the primary route for glucose uptake and hereditary defects in
GLUT1 result in seizures. GLUT1 expression is not regulated by insulin.

GLUT2 (SLCA2; choice B) is found in the liver, pancreatic β-cells, and the basolateral
surface of the small intestine and renal proximal convoluted tubule. It is a glucose
transporter with a high capacity (high Vmax) but low affinity (high Km). GLUT2 expression
is not regulated by insulin.
GLUT3 (SLCA3; choice C) localizes primarily to neuronal axons and dendrites. It is
also found in the placenta and testes. This form of glucose transporter has a very high
affinity for glucose (low Km). The named cells and tissues will, therefore, uptake glucose
at low concentrations of plasma glucose. GLUT3 is not responsive to insulin levels.
GLUT5 (SLCA5; choice E) is found in the small intestine, testes, and sperm; low levels
are also found in the kidneys, skeletal muscle, adipose tissue, and brain. It functions as
a fructose transporter. GLUT 5 is not responsive to insulin levels.
The table below summarizes the various GLUT transporters.
Name Tissues Km, Functions
Glucose
GLUT Most tissues ∼ 1 mM Basal uptake of glucose
1 (brain, red blood
cells)
GLUT Liver, ∼ 15 mM Uptake and release of
2 pancreatic β-cells glucose by the liver β-cell
glucose sensing
GLUT Most tissues ∼ 1 mM Basal uptake
3
Name Tissues Km, Functions
Glucose
GLUT Skeletal muscle, ∼ 5 mM Insulin-stimulated glucose
4 adipose tissue uptake; stimulated by
exercise in skeletal muscle
GLUT Intestine, testes, ∼10-15 mM Specific transporter for
5 sperm (fructose) fructose with no ability to
transport glucose
During an investigational study, an assay is set up to determine the amount of a hypothetical
enzyme in biological samples. Enzyme activity is measured by adding increasing amounts of
substrate to an otherwise optimal incubation system. The data obtained are shown. [S] is the
substrate concentration. Vo is the initial velocity.
[S](mM) Vo (mM/sec)
0.10 0.20
0.30 0.60
0.50 1.00
0.70 1.22
1.00 1.51
1.20 1.66
1.50 1.90
2.00 2.15
2.50 2.29
3.00 2.30
Which of the following substrate concentrations is most suitable for determining the amount of
the hypothetical enzyme?
Incorrect Answer Image
ReKap
 Vmax is the maximum initial velocity achievable with a given amount of enzyme. The only
way to increase Vmax is by increasing [S].
 By using a substrate concentration that produces an initial velocity close to Vmax, the
initial velocity will be proportional to the amount of enzyme in the assay and will
minimally change if the substrate concentration decreases during the reaction.
Analysis
The correct answer is E. At the substrate concentration ([S]) of 3.00 mM, the reaction
rate approaches Vmax and the initial velocity of the reaction changes minimally with
changes in [S]. At Vmax, the initial velocity will be directly proportional to the amount
of enzyme in the assay and will not change with small changes in substrate
concentration. Thus this is a suitable substrate concentration for conducting assays of
enzymes.
0.30 mM (choice A) is in the range of first-order kinetics with respect to [S]. The initial
velocity will depend on both [S] and the amount of enzyme in the assay.
1.20 mM (choice B) provides an activity that is slightly greater than half V max. The initial
velocity will depend on both [S] and the amount of enzyme in the assay.
1.50 mM (choice C), and 2.00 mM (choice D), generate activities of no particular
significance for interpretation. However, in these [S] ranges, the initial velocity will
still depend on both [S] and the amount of enzyme in the assay.

A 6-year-old boy is brought to the physician because of concerns about developmental delay and
behavioral issues at school. Physical examination shows an elongated face with large, protruding
ears, flat feet, and hypotonia. His mother states that his brother has a similar condition, although
his three sisters appear to be unaffected. This child's condition is most likely caused by which of
the following genetic defects?
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ReKap
 Fragile X syndrome is due to a CGG trinucleotide repeat expansion. (These are also known as
"triplet repeats.")
 Characteristics of Fragile X syndrome include developmental delay, behavioral issues, elongated

face, large protruding ears, flat feet, and hypotonia.
Analysis
The correct answer is A. This child possesses the traits associated with Fragile X syndrome. This disorder
is characterized by developmental delay and behavioral issues, as well as physical features such as an
elongated face, large protruding ears, flat feet, and hypotonia. Fragile X syndrome is caused by
a CGG trinucleotide repeat expansion in the 5' untranslated region of the FMR1 gene on the X
chromosome. The expansion causes a loss of function of the fragile X mental retardation protein.
Fragile X is the most common hereditary form of intellectual disability.
Genomic imprinting on chromosome 15 (choice B) relates to Prader-Willi and Angelman syndromes.

Prader-Willi is associated with intellectual delay, obsessive/compulsive behavior, short stature,
hypogonadism, and severe obesity due to a voracious appetite. It is caused by the deletion of several
genes on the paternally derived chromosome 15. Angelman syndrome results from deletion of the
same segment of the maternally derived chromosome 15 and presents with intellectual disability,
speech impairment, seizures, ataxia, and handflapping behavior. Patients with this disorder often have a
happy, excitable demeanor.
Microdeletion on chromosome 22 (choice C) causes DiGeorge syndrome (also known

as velocardiofacial syndrome), which is the most common microdeletion syndrome. A deletion
of 22q11.2 results in cardiac abnormalities, abnormal facies, thymic aplasia, cleft palate, and
hypocalcemia/hypoparathyroidism.
Mutation in the MECP2 gene (choice D) causes Rett syndrome, which presents with intellectual

disability in females. It is characterized by developmental regression around 12 months of age followed
by the appearance of stereotypic handwringing movements.
Trisomy of chromosome 21 (choice E) results in Down syndrome. Individuals with this disorder
are intellectually disabled, commonly have congenital heart defects, and are at increased risk for the
development of leukemia and Alzheimer's disease. In addition, they have very distinct physical features
including single palmar creases, slanted eyes, Brushfield spots of the iris, epicanthal folds, large
protruding tongue, and short stature.
A wheelchair-bound 20-year-old man is brought to the emergency department because of fatigue
and shortness of breath. Physical examination shows he has clusters of bright red blood vessels
on the sclera of both eyes. A chest x-ray shows a large mediastinal mass, which is subsequently
identified as non-Hodgkin lymphoma. Which of the following DNA repair mechanisms is most
likely defective in this patient’s cells?
ReKap
 Ataxia-telangiectasia is characterized by telangiectasias of the skin and eyes, variable

immunodeficiency, and progressive ataxia.
 The ataxia-telangiectasia gene (ATM) codes for a DNA-dependent protein kinase
responsible for recognizing and correcting DNA double-strand breaks.
 Mutation of the ATM gene causes increased sensitivity to ionizing radiation and defective
DNA repair associated with frequent chromosomal abnormalities.
 The incidence of lymphoreticular malignancies (Hodgkin and non-Hodgkin lymphomas
and leukemias) is increased.
Analysis
The correct answer is C. This patient possesses the traits associated with ataxia-
telangiectasia, including telangiectasias of the skin and eyes, variable
immunodeficiency, and progressive ataxia. Most patients are wheelchair-bound by
adolescence.
The gene responsible for the disease is called ATM and is classified as a tumor
suppressor gene that encodes a DNA-dependent protein kinase localized mainly to
the nucleus. This kinase is involved in the process that is responsible for
recognizing double-strand DNA breaks and initiating the appropriate repair
mechanisms. With the mutation of ATM, cells have increased sensitivity to ionizing
radiation, and exhibit defective DNA repair associated with frequent chromosomal
abnormalities. Therefore, these individuals should avoid unnecessary x-ray exposures.
The incidence of malignancy is high, especially lymphoreticular malignancies (Hodgkin
and non-Hodgkin lymphomas and leukemias).

Unresolved DNA replication errors can lead to mismatched base pairs (choice A).
These mismatches are normally identified by a protein complex that can recognize the
bulge in the DNA molecule that is created by the mismatched bases. Once identified,
the mismatch is then repaired by a separate complex with exonuclease activity. A
mutation in one or more of these genes ultimately leads to an accumulation of DNA
mutations due to the inability to eliminate the mismatches. Hereditary nonpolyposis
colorectal cancer (Lynch syndrome) is a disease caused by mutations in genes
involved in mismatch repair, including MSH2 and MLH1. These individuals have an
increased risk of colorectal cancers and endometrial cancers.
During DNA replication, if the DNA polymerase inserts the incorrect nucleotide, it has
the ability to correct the error. This process is known as DNA polymerase
proofreading (choice B), and is due to the polymerase’s 3' to 5' exonuclease activity.
Mutations that affect the proofreading function of DNA polymerase are associated with
an increased risk of colorectal cancers.
Defects in either nitrogenous base excision (choice D) or nucleotide base
excision (choice E) can result in xeroderma pigmentosum. This disease is
characterized by extreme sensitivity to ultraviolet light, resulting in excessive freckling,
skin cancers, and corneal ulcerations. Exposure to the sun results in thymine
dimers along the DNA. Normally, the molecules involved with these repair mechanisms
create nicks in the phosphodiester bonds flanking the thymine dimers, resulting in their
removal. In xeroderma pigmentosum, mutations in the genes responsible for these
activities (XPA, XPB, XPC, etc.) allow the thymine dimers to persist.

 The smooth endoplasmic reticulum (SER) is the site of steroid hormone and other fatty
biomolecule synthesis.
 Cells that are actively synthesizing steroid hormones (such as the testes, ovaries, and
adrenal cortex) have abundant SER.
 During pregnancy, the corpus luteum dramatically increases its progesterone production
and must expand relevant organelles such as the SER to accommodate this increased
production.
Analysis
The correct answer is E. The structure illustrated is smooth endoplasmic
reticulum (SER), which is a network of membranous sacs, vesicles, and tubules
continuous with the rough endoplasmic reticulum, but lacking ribosomes. SER contains
enzymes involved in the biosynthesis of phospholipids, triglycerides, and sterols,
including steroid hormones. Luteal cells actively
synthesize progesterone and estrogens (estradiol, estrone, and estriol) and
consequently develop abundant SER. SER additionally can function in detoxification
reactions, glycogen degradation, gluconeogenesis, and lipoprotein particle assembly.

Beta-oxidation of very-long-chain fatty acids (choice A) occurs in peroxisomes.
Degradation of DNA (choice B) occurs in lysosomes.
Oxidative phosphorylation (choice C) occurs in mitochondria.
Post-translational modification of proteins (choice D) occurs in the Golgi apparatus.
 Edwards syndrome (trisomy 18) is characterized by multiple congenital anomalies,

including clenched fists with overlapping fingers, a prominent occiput, inward-turning
"rocker-bottom" feet, congenital heart defects, low-set ears, micrognathia, and severe
intellectual disability.
 Edwards syndrome patients usually have a very poor prognosis, with death often
occurring in the first year.
Analysis
The correct answer is D. This is trisomy 18, also known as Edwards syndrome,
which is the second most common autosomal trisomy observed in live births (1 in 6000
live births) after trisomy 21. There is a relationship between meiotic nondisjunction and
advanced maternal age as with trisomy 21. The patient in this case is male, but there is
a 3:1 female predominance.
The phenotype described in the question stem is typical. Affected individuals often have
intrauterine growth retardation and low birth weight. They show failure to thrive and
feeding problems. These babies often have multiple congenital anomalies including
those involving the heart and kidneys. They have severe intellectual disability,
micrognathia (small jaw), a prominent occiput, low-set ears, short neck, rocker-bottom
feet, and clenched hands with overlapping fingers. These babies have a very poor
prognosis and most die by 1 year of age. Very low beta hCG and a very low PAPP-A
(pregnancy-associated plasma protein A) is characteristic in the first trimester. Quad
screening in the second trimester typically shows decreases in AFP (alpha-fetoprotein),
uE3 (unconjugated estriol), inhibin A, and beta hCG.
Common characteristics seen in an infant with Edwards syndrome (trisomy 18).
47,XXY (choice A) is Klinefelter syndrome, which leads to males with tall stature,
testicular atrophy, gynecomastia, a eunuchoid body habitus, a high-pitched voice, and
female distribution of hair. It often goes unnoticed in early life and is usually diagnosed
during workup for infertility.
Triple X (choice B) causes apparently phenotypically normal women; it is usually not
diagnosed in newborns.
Trisomy 13 (choice C) is Patau syndrome. It produces many midline defects, including
holoprosencephaly (embryologic failure of the brain to develop into two hemispheres)
and cleft lip and palate. Microphthalmia (small eyes), microcephaly, cardiac and renal
defects, polydactyly (6 fingers), and severe intellectual disability also occur.

Trisomy 21 (choice E) is Down syndrome, the most common trisomy in live births. It is
characterized by intellectual disability, flat face low-bridged nose, epicanthal folds,
Brushfield spots (speckled appearance) of the irises, palmar simian creases, and
congenital heart defects. There is an increased risk of early Alzheimer disease
(chromosome 21 contains amyloid precursor protein gene), acute myeloid leukemia
(AML), acute lymphoblastic leukemia (ALL), Hirshsprung disease, and duodenal atresia
(“double-bubble”) sign.
A couple from a remote town in rural Pennsylvania comes to the physician with their 4 children.
Both parents have a normal complexion with brown hair. Of their 4 children, 2 have brown hair
with fair skin and 2 have white hair and skin and light blue eyes. Physical examination of the 2
lighter children (black circle and square in the pedigree) shows nystagmus and strabismus. The
family pedigree is shown. Which of the following is the probability that IV-3 is a carrier of this
trait?
ReKap
 For an autosomal recessive condition, if a phenotypically normal child is born to parents

that are both heterozygous for the condition, we can eliminate the possibility that they are
affected. Therefore, the probability that the child is a carrier for the condition becomes
2/3.
Analysis
The correct answer is D. Albinism is an autosomal recessive disorder generally
characterized by a defect in the tyrosinase enzyme, resulting in an inability to
produce melanin. In general, autosomal recessive inheritance patterns show skipping
of generations with unaffected parents having affected offspring, as shown in this
pedigree.
In addition, this pedigree reflects the higher prevalence of autosomal recessive
diseases in the offspring of consanguineous mating. The Punnett square below
shows the frequency of genotypes for offspring of two heterozygous parents.
There would be a 25% chance that they would be normal, 50% chance that they would
be carriers, and 25% chance that they would be affected. Since we know IV-3 and IV-4
are not affected, we can disregard that probability (25%). This means that we are now
dealing with the remaining 75%, and that the original 50% chance of IV-3 being a
carrier, divided by the remaining 75% (0.50/0.75) now equals 66%, or 2/3
 DiGeorge syndrome is associated with abnormal development of the third and fourth
pharyngeal pouches. The majority of patients have a deletion on chromosome 22.
 The classic presentation for DiGeorge syndrome is the triad of cardiac anomalies,
hypoplastic thymus, and hypocalcemia from parathyroid hypoplasia.
 They also have distinct facial anomalies.
Analysis
The correct answer is A. DiGeorge syndrome is caused by malformation of
the third and fourth pharyngeal pouches, leading to the absence of
the thymus and parathyroid glands. It was originally believed that DiGeorge
syndrome was an acquired abnormality, but recent studies suggest that deletions of
chromosome 22q11 are frequently involved.
Infants afflicted with this syndrome present as dysmorphic babies who develop
convulsions or tetany a short time after birth due to severe hypocalcemia caused by a
lack of parathyroid hormone. Low ionized calcium in the extracellular fluid increases
sodium ion permeability in the neuronal membranes, resulting in increased action
potential and contraction of peripheral skeletal muscles.
A mnemonic to help remember the features associated with this 22q11 deletion
syndrome is CATCH22: Cardiac anomalies, Abnormal facies, Thymic aplasia, Cleft
palate, Hypoparathyroidism, chromosome 22.
These patients are very difficult to manage and frequently have severe
associated cardiac defects that may lead to death. Survivors often have at least small
amounts of residual thymic tissue and have few circulating T cells, making them prone
to fungal and viral infections. Antibody production, however, is usually adequate.
Monosomy of chromosome 5 (choice B) is not compatible with life. Chromosome 5 is a
large chromosome accounting for almost 6% of total DNA in cells. It is estimated to
code for between 900 and 1300 genes.
Translocation of chromosome 21 (choice C) has been associated with several cancers
including acute lymphoblastic leukemia and acute and chronic myeloid
leukemias. Robertsonian translocation can also contribute to Down syndrome
(t14,21).
Trisomy 13 (choice D) (Patau syndrome) is characterized by severe intellectual
disability and physical abnormalities including heart defects, hypotonia, microphthalmia,
cleft lip and palate, genito-urinary defects, and extra digits and toes. Only 5 to 10% of
children born with the condition survive the first year.
Trisomy of the X chromosome (choice E) is characterized by an extra X chromosome in
each of the female's cells. This chromosomal constitution typically causes no unusual
physical features. Triple X syndrome has been associated with an increased risk of
learning disabilities, speech and language delays, and delayed motor skills. Triple X can
also be seen in some forms of Klinefelter syndrome (XXXY).

eKap
 DiGeorge syndrome is associated with abnormal development of the third and fourth
Analysis

(t14,21).
A 2-day-old newborn develops tetany in the newborn nursery. His temperature is 35.9°C
(96.7°F), pulse is 120/min, and respirations are 35/min. Physical examination shows cleft palate,
wide-set eyes, micrognathia, short philtrum, broad nasal bridge, and low-set ears. The 32-year-
old mother and 5-year-old sibling have similar facial features to the newborn. Laboratory studies
show:
Erythrocyte count 4.5 million/mm3
Hematocrit 46%
Platelet count 400,000/mm3
Sodium 140 mEq/L
Potassium 4.2 mEq/L
Calcium 3.2 mg/dL
Which of the following chromosomal abnormalities is most likely responsible for the findings
seen in this patient?

DiGeorge syndrome is associated with abnormal development of the third and fourth
Analysis

(t14,21).

A 48-year-old woman with a history of intellectual disability is brought to the emergency
department by her caregivers because of a 2-week history of fever, chills, and productive cough.
They also report that she has been showing signs of memory loss and depression recently. She is
admitted to the hospital, and five days later she dies, despite appropriate treatment.
Neuropathologic examination of her brain shows neuritic plaques and neurofibrillary
tangles. Genetic analysis of this patient would most likely reveal which of the following?
ReKap
 Down syndrome (DS) is the most common chromosomal abnormality among live-
born infants. DS is most often due to a numerical alteration of chromosome 21,
with a lesser percentage of cases due to structural alterations (Robertsonian
translocation).
 Premature senility associated with neuropathologic findings characteristic of
Alzheimer disease affects Down syndrome patients several decades earlier
than the typical age of onset in the general population.
Analysis
The correct answer is B. Although the large majority (95%) of Down syndrome
(DS) is due to trisomy 21, a small percentage (4%) is due to Robertsonian
translocation (see figure). This form of translocation is due to the loss of short p arms
and the fusion of q arms of two acrocentric chromosomes. When one parent contains
such a translocation, he may pass onto his child the normal chromosome 21 and the
combination chromosome 14-21. The other parent then transmits a normal
chromosome 21, resulting in the child being diploid for chromosome 14 but triploid for
chromosome 21 (DS).
A Robertsonian translocation.
Features of DS in children include intellectual disability, epicanthal folds, dysplastic
ears, hypotonia, a horizontal palmar crease (simian crease), redundant neck skin,
and a short trunk. Congenital heart disease is present in about 1/3 of liveborn DS

infants. Additional malformations are more common in DS, including duodenal
atresia and tracheoesophageal fistula. There is a 15–fold increase in leukemia.
Individuals with DS develop clinical dementia with clinical and pathologic characteristics
that are virtually identical to Alzheimer disease (AD). Autopsy findings
include intraneural neurofibrillary tangles, extracellular neuritic plaques, amyloid
beta (Abeta) protein in senile plaques, and amyloid angiopathy. There are some
differences because this neuropathology is superimposed on brain pathology unique to
DS. One important clinical difference is the early age of onset of AD with DS patients.
There is no treatment and prognosis is poor. AD causes a sharp decline in survival in
DS patients older than 45 years. Many genes coding for proteins likely involved in AD
development such as amyloid precursor protein (APP) and superoxide dismutase
(SOD-1) are located on chromosome 21. The overexpression of these genes due to
trisomy 21 is likely responsible for the early AD.
Patients with the other listed conditions are not particularly prone to early AD:
Common features of 45, X0 (choice A) also known as Turner syndrome include short
stature, webbed neck, lymphedema in hands and feet, skeletal abnormalities,
congenital heart defects, coarctation of the aorta, and infertility. Individuals may have
learning disabilities though intelligence is usually normal.
47, +13 (choice C), also known as Patau syndrome or trisomy 13, is characterized by
severe intellectual disability, microcephaly, microphthalmia, polydactyly, cleft lip and
palate, renal defects, and cardiac abnormalities. Affected infants typically die before the
age of 1 year.
Fragile X syndrome (choice D) can occur in males and females although females often
have milder symptoms. It is associated with enlarged testes after puberty
(macroorchidism) as well as intellectual disability, large ears, prominent jaw and
forehead. The condition is unusual in that it is related to expansion of a CGG repeat
sequence located on the X chromosome, which leads to a loss of function mutation in
the Fragile X Mental Retardation 1 (FMR1) gene.
Patients with Klinefelter syndrome (47, XXY) (choice E) are male and have impaired
sexual development. They typically have small testes that are not able to produce
sufficient amounts of testosterone, resulting in delayed or incomplete puberty,
gynecomastia, undescended testes, micropenis, and infertility. As adults, they tend to
be taller than their peers.
Updated on 03/31/21
A 35-year-old person who is a marathon runner experiences cutaneous vasodilation to help cool their
body while running on a hot summer day. Increased blood flow leads to the release of a chemical
mediator from endothelial cells that causes vasodilation in arterioles. Which of the following enzymes is
directly activated by this chemical mediator
ReKap
Nitric oxide (NO):
 Short-acting physiologic messenger.

 After release, NO 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.
Analysis
The correct answer is B. Nitric oxide (NO) is a short-acting (about 100 msec)
physiologic messenger that is released from endothelial cells. NO diffuses to
nearby smooth muscle cells, enters the cells, and activates soluble (cytosolic)
guanylate cyclase. Guanylate cyclase makes the second messenger cGMP, which
triggers smooth muscle relaxation by facilitating the dephosphorylation of
myosin light chains. This prevents the interaction of myosin with actin. This is also the
mechanism by which NO causes vasodilation in the corpus cavernosum of the penis,
leading to penile erection.
ReKap
Nitric oxide (NO):
 Short-acting physiologic messenger.

 After release, NO 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.
Analysis
The correct answer is B. Nitric oxide (NO) is a short-acting (about 100 msec)
physiologic messenger that is released from endothelial cells. NO diffuses to
nearby smooth muscle cells, enters the cells, and activates soluble (cytosolic)
guanylate cyclase. Guanylate cyclase makes the second messenger cGMP, which
triggers smooth muscle relaxation by facilitating the dephosphorylation of
myosin light chains. This prevents the interaction of myosin with actin. This is also the
mechanism by which NO causes vasodilation in the corpus cavernosum of the penis,
leading to penile erection.
The figure above details the action of nitric oxide (NO). Overall, the effect of nitric oxide
promotes smooth muscle relaxation.
Adenylate cyclase (choice A) is a plasma membrane-bound enzyme that is activated
by a ligand binding to a Gs protein-coupled receptor. This enzyme converts ATP
into cAMP and PPi. cAMP, a second messenger, activates protein kinase A.
Heme oxygenase (choice C) is the enzyme that converts heme to bilirubin. It cleaves
cyclic heme to linear biliverdin, releasing free iron and carbon monoxide in the
process. Biliverdin reductase converts biliverdin to bilirubin.
NO synthase (NOS; choice D) synthesizes NO from arginine. The reaction requires
NADPH and oxygen as substrates, and produces NO and citrulline. There are three
isoforms of NOS: endothelial (eNOS) and neuronal (nNOS), which are constitutively
expressed and respond to a rise in calcium, and inducible (iNOS) that is independent of
calcium levels. iNOS is induced in response to bacterial infection. In addition to its role
in vasodilation, NO is a neurotransmitter.
Phospholipase C (choice E) cleaves phosphatidylinositol bisphosphate
(PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3). IP3 causes
the release of calcium from the endoplasmic reticulum, and DAG activates protein
kinase C. This cascade of events is initiated by the binding of a ligand to a G q protein-
coupled receptor.
Summary of signal transduction by water-soluble hormones:
Pathwa G Enzyme Second Protein Examples

y Protein Messenger Kinase
s)
cAMP GS(Gi) Adenyl cAMP Protein  Glucagon
cyclase kinase  Epinephri
A ne (β, α-
2)
 Vasopres
sin (V2,
ADH)
Pathwa G Enzyme Second Protein Examples
y Protein Messenger Kinase
s)
 kidney
PIP2 Gq Phospholipa DAG, IP3, Protein  Vasopres
se C Ca2+ kinase sin (VI,
C V3)
vascular
smooth
muscle
 Epinephri
ne (α1)
cGMP None Guanylate cGMP Protein  Atrial
cyclase kinase natriureti
G c factor
(ANF)
 Nitric
oxide
(NO)
Insulin, Monomer –– –– Tyrosin  Insulin
growth ic p21ras e  Insulin-
factors kinase like
activity growth
of factor
recepto (IGF)
r  Platelet-
derived
growth
factor
(PDGF)
 Epiderma
l growth
factor
(EGF)
ReKap
 Fabry disease is an X-linked, recessive, inherited inborn error of the glycosphingolipid

metabolic pathway.
 Onset is usually during late childhood or adolescence.
 Severe neurologic deterioration is present in most sphingolipid storage diseases (except
Gaucher disease, which tends to affect the liver and spares the brain).
Analysis
The correct answer is A. Fabry disease is a lysosomal storage disease resulting
from the absence of alpha-galactosidase A. The clinical presentation includes:
 Burning sensations in the hands which get worse with exercise and hot weather.
 Small, raised reddish-purple blemishes on the skin (angiokeratomas).
 Eye manifestations, especially cloudiness of the cornea.
 Impaired arterial circulation and increased risk of myocardial infarction or stroke.
 Enlargement of the heart and kidneys.
 Renal failure is often the cause of death.
For this question, even if you cannot remember the features of the individual lipid
storage diseases, it is worth remembering that Fabry disease is the only X-linked lipid-
storage disease; the rest are autosomal recessive. As a general rule, associate all of
the lipid storage diseases with severe neurologic deterioration. The exception is
Gaucher disease (choice B), which tends to affect the liver and spares the brain.
Characteristics of X-linked recessive inheritance includes:
 More frequent in males because males require only one copy of the mutation to express
the disease, whereas females require 2 copies.
 Skipped generations are common because an affected male can transmit the disease-
causing mutation to a heterozygous daughter who is unaffected, but who can transmit the
disease-causing allele to her sons.
 Male-to-male transmission is not seen; this helps distinguish it from autosomal
inheritance.
Gaucher disease (choice B) is an autosomal recessive lipid storage disease caused by
a deficiency in the enzyme glucocerebrosidase. Findings generally include
hepatosplenomegaly, bone abnormalities, and Gaucher cells. The disease is more
prevalent in individuals of Ashkenazi Jewish descent.

Associate Krabbe disease (choice C) with the presence of "globoid" cells in
degenerating cerebral white matter, as well as peripheral neuropathy. The enzyme
affected in this disease is galactocerebrosidase. Krabbe disease follows an autosomal
recessive inheritance pattern.
Metachromatic leukodystrophy (choice D) is caused by a deficiency of the
enzyme arylsulfatase A, and follows autosomal recessive inheritance. Patients present
with ataxia and dementia.
Niemann-Pick disease (choice E), and Tay-Sachs disease (choice F) are autosomal
recessive lysosomal storage diseases. Niemann-Pick disease is caused by a deficiency
in sphingomyelinase and Tay-Sachs is caused by a deficiency in hexosaminidase A.
They both involve findings of a cherry red spot on the macula but are differentiable by
the presence or absence of hepatosplenomegaly (presence of hepatosplenomegaly in
Niemann-Pick, absence of hepatosplenomegaly in Tay-Sachs). Both diseases occur
with greater frequency in Ashkenazi Jews.

 Hemophilia A and B are X-linked recessive diseases due to mutations in clotting factors
VIII and IX, respectively.
 For X-linked recessive disorders, all of the daughters of an affected male will be carriers.
 In rare cases, X-chromosome inactivation in females can lead to a predominance of the
affected allele, leading to a mild form of X-linked recessive disease.
Analysis
The correct answer is D. Hemophilia is a group of genetic disorders caused by
mutations in the genes that encode blood clotting factors. Individuals with this disease
can have both internal and external bleeding episodes. Hemophilia A is due to a
deficiency of clotting factor VIII and is the most common form of the
disorder. Hemophilia B, or factor IX deficiency, is less common, but presents with
similar clinical symptoms.
The genes that encode for these two clotting factors lie on the X chromosome and are
inherited in an X-linked recessive fashion. This means that an affected male will pass
on his mutated X chromosome to all of his daughters (as is the case here), but none of
his sons will have the mutation since those individuals would have inherited his
unaffected Y chromosome.
In females, one X chromosome is randomly inactivated in each cell during
embryogenesis. This results in some cells having only an active paternal X
chromosome and some cells only having an active maternal X chromosome. This
patient likely has more cells with active paternal X chromosomes (mutated) than
maternal (non-mutated), thus producing a mild form of hemophilia. This is referred to as
"skewed X chromosome inactivation" in which one of the two X chromosomes is
active in slightly greater than half of the cells in the body and the other X chromosome is
active in slightly less than half of the cells. If this patient were to have children, her sons
would have a 50% chance of inheriting her affected X chromosome, and those that do
would have a more severe form of the disease.
Because only male offspring are affected by this disorder, it is not likely that this is an
autosomal dominant (choice A) or autosomal recessive (choice B) disorder. In both
autosomal dominant and autosomal recessive disorders, males and females have an
equal chance of inheriting the mutant allele. Autosomal dominant disorders are further
characterized by the presence of the disease in all generations, whereas autosomal
recessive tends to skip generations due to the lower probability that offspring will inherit
two affected alleles. An example of an autosomal dominant disorder is achondroplasia,
a form of short-limbed dwarfism. There are many examples of autosomal recessive
disorders, including Tay-Sachs disease and cystic fibrosis.
The inheritance pattern of mitochondrial (choice C) diseases is more complex. These
diseases are due to mutations in the mitochondrial DNA rather than the nuclear DNA.
Since cells have many copies of mitochondria, the ratio of mutated organelles to non-
mutated organelles dictates the severity of these diseases. Mitochondria are inherited
from the mother, so these diseases are passed from mother to all offspring. Since this
individual appears to have inherited hemophilia from her father, this disease does not
follow a mitochondrial mode of inheritance.
There are relatively few Y-linked (choice D) disorders, including a form of retinitis
pigmentosa. Since the affected individual, in this case, is female, it cannot be a Y-
linked disorder.
An 18-month-old girl is brought to the physician because her family noticed that in a certain
light, the pupil of her left eye appears white. An ophthalmologic examination shows a tumor in
her left eye. She is diagnosed with retinoblastoma. Which of the following tests best determines
whether this resulted from an inherited mutation or a somatic mutation in the RB1 gene?
ReKap
 PCR is the test of choice to determine the sporadic or heritable nature of retinoblastoma.
 In inheritable retinoblastoma, one chromosome will show a mutation in all the cells of the
body. Sequencing of the PCR product would be required for non-deletion mutations.
 In sporadic retinoblastoma, cells other than the tumor will show the normal two alleles.
 Sequencing of the PCR product from non-tumor cells will allow the distinction between
sporadic and hereditary retinoblastoma to be determined.
Analysis
The correct answer is D. One of the first signs of retinoblastoma is leukocoria, which
means "white pupil." It is most often initially noticed by close family members or on flash
photography and is often the reason for consultation.
 40% of retinoblastomas are heritable; the child inherits one mutant allele through the
germline and a somatic mutation in the other allele occurs at some point during retinal
development, resulting in the loss of function of that gene. This leads to tumor
development. In these cases, the disease is often bilateral and multifocal.
 60% of retinoblastomas are sporadic; both alleles are inactivated by somatic mutation
within the same cell. These are unilateral and unifocal and tend to be diagnosed later
than heritable cases (an average of 24 months vs 12 months).
To detect a mutation in the RB1 gene and differentiate between heritable and sporadic
cases of retinoblastoma, PCR is the most appropriate technique of the choices given.
Using the appropriate primers, a deletion can be detected as a change in size of the
DNA band amplified. A single base mutation can be detected by sequencing the PCR
product.
 In inheritable cases, one chromosome will have an altered length as a result of the
deletion and this mutation will be present in all cells.
 In sporadic retinoblastoma, samples isolated from sites other than the tumor should have
two normal alleles.
 Not all mutations in retinoblastoma are deletions. In these cases, PCR would be followed
by sequencing the PCR products to identify the mutation causing retinoblastoma.
The following table compares inherited and sporadic retinoblastoma:
Inherited Retinoblastoma Sporadic Retinoblastoma

Many tumors in both eyes One tumor in one eye
Many tumors in other parts of the Tumors occur in other organs at the
body same rate as in the general population
Mutations are passed to offspring in Mutations are not passed to offspring
autosomal dominant fashion
Enzyme-linked immunosorbent assay (ELISA) (choice A) is a highly sensitive assay
that can be used to identify the presence of an antibody against a specific antigen or
protein. ELISA cannot be used to distinguish between a sporadic or heritable form of
cancer.
FACS (choice B) uses antibodies coupled to fluorescent markers to determine cell
surface molecules on intact cells. It is very useful for determining the stage of
development or activation of cells (e.g., detection of CD antigens on cells in the immune
system), but does not give any insight into the DNA sequence or length.
Northern blotting (choice C), the RNA counterpart to Southern blotting, is used to
determine the size and abundance of mRNA transcribed from a specific gene in a
given sample of RNA. Northern blot analysis is typically used to compare gene
expression levels between different tissues, and to detect splice variants.
Western blotting (choice E) is the protein counterpart of Southern and Northern
blotting. Western blotting is useful to determine whether a protein is present or absent
in a patient, or if it is the wrong size, suggesting an error in the DNA for this protein.
However, Western blotting would not easily be able to determine the precise nature of
the relevant mutant gene.

The correct answer is D. One of the first signs of retinoblastoma is leukocoria, which
means "white pupil." It is most often initially noticed by close family members or on flash
photography and is often the reason for consultation.
 40% of retinoblastomas are heritable; the child inherits one mutant allele through
the germline and a somatic mutation in the other allele occurs at some point
during retinal development, resulting in the loss of function of that gene. This
leads to tumor development. In these cases, the disease is often bilateral and
multifocal.
 60% of retinoblastomas are sporadic; both alleles are inactivated by somatic
mutation within the same cell. These are unilateral and unifocal and tend to be
diagnosed later than heritable cases (an average of 24 months vs 12 months).
To detect a mutation in the RB1 gene and differentiate between heritable and sporadic
cases of retinoblastoma, PCR is the most appropriate technique of the choices given.
Using the appropriate primers, a deletion can be detected as a change in size of the
DNA band amplified. A single base mutation can be detected by sequencing the PCR
product.
 In inheritable cases, one chromosome will have an altered length as a result of

the deletion and this mutation will be present in all cells.
 In sporadic retinoblastoma, samples isolated from sites other than the tumor
should have two normal alleles.
 Not all mutations in retinoblastoma are deletions. In these cases, PCR would be
followed by sequencing the PCR products to identify the mutation causing
retinoblastoma.
The following table compares inherited and sporadic retinoblastoma:
Inherited Retinoblastoma Sporadic Retinoblastoma

Many tumors in both eyes One tumor in one eye
Many tumors in other parts of the Tumors occur in other organs at the
body same rate as in the general population
Mutations are passed to offspring in Mutations are not passed to offspring
autosomal dominant fashion
Enzyme-linked immunosorbent assay (ELISA) (choice A) is a highly sensitive assay
that can be used to identify the presence of an antibody against a specific antigen or

protein. ELISA cannot be used to distinguish between a sporadic or heritable form of
cancer.
FACS (choice B) uses antibodies coupled to fluorescent markers to determine cell
surface molecules on intact cells. It is very useful for determining the stage of
development or activation of cells (e.g., detection of CD antigens on cells in the immune
system), but does not give any insight into the DNA sequence or length.
Northern blotting (choice C), the RNA counterpart to Southern blotting, is used to
determine the size and abundance of mRNA transcribed from a specific gene in a
given sample of RNA. Northern blot analysis is typically used to compare gene
expression levels between different tissues, and to detect splice variants.
Western blotting (choice E) is the protein counterpart of Southern and Northern
blotting. Western blotting is useful to determine whether a protein is present or absent
in a patient, or if it is the wrong size, suggesting an error in the DNA for this protein.
However, Western blotting would not easily be able to determine the precise nature of
the relevant mutant gene.
Blot Material Electrophoresis Probe Purpose

Type Analyzed Required Used
Southern DNA Yes 32
P-DNA To determine which
restriction fragments
of DNA are
associated with a
particular gene
Northern RNA Yes 32
P-DNA To measure sizes and
amounts of specific
mRNA molecules to
answer questions
about gene
expression
Blot Material Electrophoresis Probe Purpose
Type Analyzed Required Used
Western Protein Yes I-or
125
To measure amount
enzyme- of antigen (proteins)
linked or antibody
antibody
A study is conducted to determine the gene sequence for an area of the HFE gene that contains a
mutation associated with hemochromatosis. Using a primer to initiate replication of
the HFE gene and radiolabeled dideoxynucleotides to terminate synthesis, the results are shown
on the sequencing gel and compared to the normal HFE gene sequence. In the image shown, the
positive end of the gel is at the bottom.
Normal HFE sequence:
5'-TGCTGCAATGACAG-3'
Which of the following genetic changes is most likely present in the mutated HFE gene?
A.Deletion of one purine-containing nucleotide
Deletion of one pyrimidine-containing nucleotide
Insertion of one purine-containing nucleotide and deletion of one pyrimidine-containing nucleotide
Insertion of two purine-containing nucleotide

Insertion of two pyrimidine-containing nucleotides
ReKap
 A common method for sequencing DNA is known as “chain termination” or the Sanger
method.
 By convention, sequencing gels are normally read from bottom to top.
 The shorter fragments are located closest to the positive electrode of the gel (bottom), and
the longer fragments closest to the negative electrode of the gel (top).
 The nitrogenous bases adenine and guanine are purines, whereas thymine and cytosine
are pyrimidines.
Analysis
The correct answer is B. In this procedure, labeled dideoxynucleotides are added to
a sample containing amplified DNA and a special DNA polymerase. The
dideoxynucleotides randomly insert into the nascent chains and stop the synthesis at
the point of insertion (also known as chain termination), leading to DNA strands of
different lengths. Since DNA is negatively charged, the different length DNA strands
migrate at different rates on a gel and therefore separate from each other according to
size. The shortest strands travel the fastest, so form the lowest band. The type of label
on the dideoxynucleotide can be determined (often using different color fluorescent
probes), so the identity of each terminal nucleotide can be determined. This method for
sequencing DNA is known as the Sanger method.
If you read the gel for the mutated gene from the bottom, as sequencing gels are
generally read (from shortest to longest), you get TGCTGCAAGACAG. Compare this to
the normal sequence, and you see that T is missing between the A at position 8 and G
at position 10 of the normal sequence (TGCTGCAATGACAG). The nitrogenous bases
adenine and guanine are purines, and thymine and cytosine are pyrimidines.
Therefore, one pyrimidine (T) has been deleted.
None of the other choices (choices A, C, D, or E) correctly describe the genetic change
seen in the mutated gene.
Updated on 02/14/21
A 15-year-old boy is brought to the physician by his parents because of a failure to develop
normal male secondary sexual characteristics. He is above normal height for his age. Physical
examination shows small testes and gynecomastia. His parents report that he had to repeat the
8th and 9th grades and he is still struggling in his classes. This patient's condition is most likely to
be related to which of the following genetic abnormalities?
ReKap
 Klinefelter syndrome is the most common congenital abnormality causing primary

hypogonadism.
 The most common genotype is 47,XXY, resulting from nondisjunction of sex
chromosomes of either parent’s germ cells during meiotic division.
Analysis
The correct answer is C. The boy probably has Klinefelter syndrome (47,XXY),
which has the typical presentation described in the question. Klinefelter’s syndrome is
the most common congenital abnormality causing primary hypogonadism and occurs in
approximately 1 in 1000 live births. The diagnosis is commonly made during
adolescence or adulthood in males who have small testes with hypergonadotropic
hypogonadism and gynecomastia. The condition arises as a result of failure of
separation (nondisjunction) of the sex chromosomes during meiotic division, and
can be related to either paternal nondisjunction (slightly more common) or maternal
nondisjunction.
Two common symptoms leading to the diagnosis include infertility and gynecomastia.
Other symptoms include fatigue, erectile dysfunction, language impairment, academic
difficulty, subnormal libido, osteoporosis, and behavioral problems.
Two notable examples of gene deletion (choice A) are Prader-Willi and Angelman
syndromes, both of which occur on the q arm of chromosome 15. Both conditions can
present with intellectual disability. Prader-Willi syndrome can exhibit uncontrollable

appetite and increased weight, whereas Angelman syndrome would exhibit ataxia with
constant smiling and laughing ("happy puppet").
Examples of nondisjunction of autosomes (choice B) include trisomies such as most
cases of Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau
syndrome (trisomy 13).
There are two types of translocations: Reciprocal (choice D) and Robertsonian (choice
E).
 Reciprocal translocations result when two non-homologous chromosomes exchange

genetic material.
 Robertsonian translocations are a special type of translocation that involve loss of the p
arms and exchange of genetic material from the long arms of one acrocentric
chromosome to the long arms of another acrocentric chromosome, with fusion of the
centromeres. 4% of cases of Down syndrome are caused by this mechanism.
Updated on 04/19/21
A 6-month-old boy is brought to the physician by his parents, who are first cousins, for a well-
child examination. The boy appears thin, small, and lethargic. Physical examination shows
slightly misshapen long bones. Joint movements are restricted, the corneas are clouded, and the
gums are hyperplastic. Laboratory studies show elevated serum levels of acid hydrolases and
glycosylases. Which of the following is the most likely primary defect in this patient?
ReKap
 I-cell disease defect: phosphotransferase activity in the Golgi apparatus.

 Tay-Sachs disease defect: hexosaminidase A activity in the lysosome.
 Niemann-Pick disease defect: sphingomyelinase activity in the lysosome.
 Hurler disease defect: iduronidase activity in the lysosome.
Analysis
The correct answer is E. This patient has I-cell disease, also known
as mucolipidosis II, which is caused by a defective UDP-N-acetylglucosamine-1-
phosphotransferase, the enzyme that phosphorylates a terminal mannose moiety on
enzymes destined for inclusion in lysosomes. The resulting mannose-6-phosphate
residue interacts with a specific receptor on the lysosomal membrane and triggers
internalization. In the absence of mannose phosphorylation, the enzyme is secreted into
the extracellular space.
Proteins coded by nuclear DNA are synthesized on cytoplasmic ribosomes, which may
be either "free" or associated with the endoplasmic reticulum to form the rough
endoplasmic reticulum (RER). Proteins synthesized in the RER are transferred into
the Golgi apparatus, where they undergo further modifications that determine whether
they remain part of the Golgi apparatus, become part of the plasma membrane, or are
shipped to lysosomes or other locations. Proteins not marked for transport to a specific
intracellular site follow the default pathway and are exported into the extracellular
compartment. Lysosomes deprived of critical enzymes (e.g., due to I-cell disease) are
unable to degrade their normal substrates, the latter of which gradually accumulate and
transform the lysosomes into inclusion bodies.
In I-cell disease, this terminal mannose moiety is not phosphorylated, and the acid
hydrolases follow the default pathway and are secreted. Like many of the lysosomal
storage diseases, the lack of lysosomal enzymes causes structural defects in the cells.
One of the characteristics of I-cell disease is abnormal vacuolization and inclusion
bodies in the cytoplasm. By the age of 6 months, there is a failure to thrive (and other
developmental delays) as well as abnormal skeletal development, coarse facial features
and restricted joint movement.
Hexosaminidase A deficiency (Tay-Sachs disease) is one example of a condition in
which ganglioside accumulation occurs (choice A).
Deficiency of alpha-L-iduronidase results in lysosomal accumulation of dermatan sulfate
and heparan sulfate (choice B) in several conditions, such as mucopolysaccharidosis
I, Hurler disease, and Hurler-Scheie syndrome.
There are several diseases in which glycogen degradation (choice C) is defective.
These are collectively termed glycogen storage diseases because they result in
abnormal cellular accumulation of glycogen. In Pompe disease, or type II glycogen
storage disease, a lysosomal glucosidase is deficient, resulting in lysosomal glycogen
accumulation.
Deficiency of sphingomyelinase (choice D), an enzyme involved in the degradation of
sphingomyelin, results in Niemann-Pick disease.

Phosphorylation of tyrosine in tyrosine kinase receptors (choice F) is unrelated to
lysosomes or lysosomal enzymes; however, decreased ability to phosphorylate tyrosine
moieties might be associated with diabetes or dwarfism.

A 35-year-old man comes to establish care with a new physician due to progressively worsening chronic
kidney disease. He describes pain and tingling of his hands and feet that began during his early
adolescence. His blood pressure is 150/90 mm Hg and the rest of his vital signs are within normal limits.
Physical examination shows multiple dark-red macules of variable size over his lower abdomen, buttocks,
and upper thighs. The remainder of his physical examination shows no abnormalities. Laboratory studies
show BUN 30 mg/dL, serum creatinine 3.0 mg/dL, and urinalysis with 2+ protein and trace blood.
Urinary oval fat bodies with a Maltese cross configuration are seen with polarizing microscopy. These fat
bodies contain globotriaosylceramide. Which of the following is the most likely hereditary enzyme
deficiency responsible for this patient's clinical findings?
ReKap
 Fabry disease is a lysosomal storage disease resulting from the hereditary deficiency of
the enzyme alpha-galactosidase A, leading to the intracellular accumulation of
globotriaosylceramide.
 Fabry disease is an X-linked recessive disease.
 The kidneys, heart, nervous system, skin, and eyes are the commonly affected organs in
Fabry disease.
 Urinary oval fat bodies can be seen in Fabry disease and result from the large amount of
globotriaosylceramide in the urine.
Analysis
The correct answer is A. This young man has Fabry disease. This lysosomal
storage disease comprises the clinical and pathological manifestations of the
hereditary deficiency of the enzyme alpha-galactosidase A. This deficiency results in
intracellular accumulation of neutral glycosphingolipids with alpha-galactosyl moieties,
the most abundant of which is globotriaosylceramide, which results in damage to the
kidneys, heart, nervous system, skin, and eyes. Fabry disease is an X-linked
recessive disorder with severe clinical manifestations observed in hemizygous males
and heterozygous females exhibiting a variable course.
Renal involvement starts in the second decade of life with proteinuria and
microhematuria. Urinary oval fat bodies can be seen and result from a large amount of
globotriaosylceramide in the urine. Renal disease progresses to end-stage renal
disease requiring renal replacement therapy by the fourth and fifth decade of life.
Cardiac defects caused by glycosphingolipid accumulation in coronary artery
endothelial cells can lead to angina, myocardial infarction, and congestive heart failure.
Neurologic involvement causes peripheral neuropathy (acral paresthesias and
hypohidrosis) and cerebrovascular damage leading to ischemic strokes.
Angiokeratomas (dark red macules or papules of variable size) are the characteristic
skin lesions seen with Fabry disease and are typically located in the lower trunk,
buttocks, hips, and upper thighs. Corneal opacities (corneal verticillata) are the
characteristic eye manifestation and common in both males and females with Fabry
disease.
Galactocerebrosidase (choice B) is the deficient enzyme in Krabbe disease. This
autosomal recessive disorder results in the accumulation of galactocerebroside.
Clinical manifestations include peripheral neuropathy, developmental delay, optic
atrophy, and seizures.
Glucocerebrosidase (choice C) is the deficient enzyme in Gaucher disease. This
autosomal recessive disorder is the most common lysosomal storage disease and
results in the accumulation of glucocerebroside. Clinical manifestations include
peripheral neuropathy, hepatosplenomegaly, pancytopenia, diffuse bone pain,
osteonecrosis (avascular necrosis), and interstitial lung disease.
Hexosaminidase A (choice D) is the deficient enzyme in Tay-Sachs disease. This
autosomal recessive disorder results in the accumulation of GM2 ganglioside. Clinical
manifestations include progressive neurodegeneration and a "cherry-red" spot on the
macula.
Sphingomyelinase (choice E) is the deficient enzyme in Niemann-Pick disease. This
autosomal recessive disorder results in the accumulation of sphingomyelin. Clinical
manifestations include progressive neurodegeneration and a "cherry red" spot on the
macula, similar to Tay-Sachs disease. Patients with Niemann-Pick disease have
hepatosplenomegaly, which is not seen in Tay-Sachs disease.

A 38-year-old man collapses while running a marathon and is brought to the emergency
department. His wife states that he did not train or prepare for the marathon but still decided to
run. Arterial blood gas on room air shows PaO of 100 mm Hg, PaCO of 42 mm Hg, and pH of 7.30.
2 2
Further evaluation reveals a metabolic acidosis with a high anion gap. Increased activity of
which of the following biochemical pathways is the basis for this patient's clinical findings?
R eKap
 When the oxygen demand of the skeletal muscle exceeds the ability of the heart and
lungs to provide oxygen, the muscles switch to anaerobic glycolysis, where the pyruvate
produced is reduced to lactate by the action of lactate dehydrogenase.
 Lactate is then released by the cells where it enters the bloodstream, causing metabolic
acidosis with a high anion gap.
Analysis
The correct answer is A. Undewhen oxygen is readily available,
the pyruvate generated in glycolysis enters the mitochondria and is decarboxylated
to acetyl CoA by the action of pyruvate dehydrogenase. In severe exercise,
particularly by individuals in poor physical condition, the oxygen demands of the skeletal
muscle may exceed the ability of the heart and lungs to provide oxygen. Consequently,
oxidation of NADH by the electron transport chain is decreased, as is ATP production
by oxidative phosphorylation.
In this setting, the muscles switch to anaerobic glycolysis and the pyruvate that is
produced is reduced to lactate by the action of lactate dehydrogenase as NADH is
oxidized. The NAD+ generated allows glycolysis to continue and ATP is generated by
substrate-level phosphorylation. Much of the lactic acid thereby produced is released
into the bloodstream, where it causes a metabolic acidosis with a high anion gap.
In addition to the setting of severe exercise, lactic acidosis can also be seen in tissue
hypoxia (seizures, cardiac failure, hypotension, carbon monoxide poisoning, severe
anemia), with drug toxicity and toxins (phenformin, catecholamines, salicylate, isoniazid,
cyanide), in congenital defects in processes that utilize pyruvate such as
gluconeogenesis, and in many severe illnesses.
Beta-oxidation of fatty acids (choice B) can produce acetyl-CoA, which, in the liver
mitochondria, may be converted to ketone bodies such as acetoacetate and β-
hydroxybutyrate if the acetyl-CoA is not used in the citric acid cycle. When the
production of these ketone bodies exceeds their use, ketoacidosis (a type of high
anion gap metabolic acidosis) can result. This would not be expected in the patient.
The citric acid cycle (choice C) oxidizes acetyl CoA from the oxidation of glucose, fatty
acids, and some amino acids and produces CO2, NADH, and FADH2. Increasing the
activity of the cycle would not cause a metabolic acidosis.
In mitochondrial oxidative phosphorylation (choice D), the NADH and FADH2 from the
citric acid cycle (and other sources) are oxidized by the electron transport chain. The
electrons are used in the reduction of oxygen to water. Electron transport generates a
proton gradient that is used to drive ADP phosphorylation to ATP.
The pentose phosphate shunt (choice E) is an important producer of NADPH and
ribose-5-phosphate. The NADPH is used in reductive biosynthetic processes such as
fatty acid synthesis. The ribose 5-phosphate (from the isomerization of ribulose 5-P) is
used in the synthesis of phosphoribosylpyrophosphate (PRPP) required for de
novo synthesis and salvage of purine and pyrimidine bases.

This chart below shows the different uses of pyruvat
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ReKap
 Cocaine can cause cardiac ischemia, which leads myocardial cells to switch to
anaerobic metabolism.
 The rate-limiting enzyme of glycolysis is phosphofructokinase-1 (PFK-1) and its
activity would increase with a shift from aerobic (oxidative phosphorylation) to
anaerobic (substrate level phosphorylation) energy production.
Analysis
The correct answer is C. Cocaine blocks the reuptake of norepinephrine, resulting
in tachycardia, increased inotropy, increased systolic blood pressure, and
excessive vasoconstriction of the coronary vessels. These effects lead to ischemia
and infarction of heart tissue, known as contraction band necrosis. Under these
pathologic conditions, myocardial cells switch to anaerobic metabolism and, therefore,
anaerobic glycolysis becomes the major source of adenosine triphosphate (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 allosterically by the production of adenosine
monophosphate (AMP).
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 alter its kinetic properties under
hypoxic conditions or under a shift from aerobic to anaerobic metabolism.

Phosphoenolpyruvate carboxykinase (choice B) is a regulatory enzyme in
gluconeogenesis that is induced by cortisol, epinephrine, and glucagon. It functions in
the hepatic synthesis of glucose when energy levels from the beta-oxidation of fatty
acids are adequate.
Pyruvate kinase (choice D) is the terminal step of glycolysis and is not allosterically
regulated to any great extent in the heart. Under anaerobic conditions, there would be
higher levels of phosphoenolpyruvate, the substrate, which would enable more product
to be formed per unit time until the Vmax is reached. It is the liver and erythrocyte forms of
pyruvate kinase that are allosterically regulated.
Succinate dehydrogenase (choice E) is a key enzyme of the citric acid cycle, producing
a reduced equivalent of flavin adenine dinucleotide (FAD) to feed into the electron
transport chain. It is also known as Complex II. The citric acid cycle only functions if
oxygen is available in appropriate concentrations since it is regulated by the levels of
nicotinamide adenine dinucleotide (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 citric
acid cycle.
 Folic acid deficiency during pregnancy is associated with an increased risk for congenital
neural tube defects (NTD).
 Folic acid is required for the conversion of homocysteine to methionine and methionine
is converted into S-adenosylmethionine (SAM).
 Low folic acid levels, therefore, cause elevated homocysteine and low SAM.
 The drop in SAM levels will lead to hypomethylation of DNA and lipids in the nervous
system, contributing to neural tube defects in a developing fetus.
 Folic acid supplementation during pregnancy decreases homocysteine levels, increases
methionine and SAM levels, and reduces the risk of NTD.
Analysis
The correct answer is D. Homocysteine levels will decrease when the woman takes
her vitamin supplement, which is folic acid. The woman most likely has low folate
levels caused either by a vitamin deficiency or by a common polymorphism that leads to
reduced activity of N5, N10-methylenetetrahydrofolate reductase.
With a reduced ability to synthesize N5-methyltetrahydrofolate, the levels of
homocysteine will increase because the homocysteine cannot be converted
to methionine in a B12-dependent reaction. The reduced production of methionine
would lead to reduced levels of S-adenosylmethionine (SAM), leading to both gene

and lipid hypomethylation in the nervous system. The alteration of gene expression and
myelin production contributes to the development of neural tube defects in the fetus.
Due to the common genetic variant in the population women thinking about becoming
pregnant are advised to take supplemental folic acid to reduce the risk of having a child
with a neural tube defect. Folic acid is recommended for all women considering
pregnancy at a dose of 0.4–0.8 mg daily, and the dose should be increased to 4 mg
daily in women with a history of a prior pregnancy with a neural tube defect. Once folate
is given to the patient the homocysteine levels will decline as it is converted to
methionine, as shown in the figure.
Folate derivatives help in the synthesis of purines and thymidine. Folate must be
reduced into tetrahydrofolate (THF) and a 1-carbon unit is added to THF, which can
lead to various kinds of one-carbon units (formyl, methenyl, methylene). Various forms
of THF can go through important pathways including purines and thymidine synthesis.
S-adenosylmethionine (choice A) is incorrect because SAM levels will also increase
once the patient's folate levels are normalized, for as soon as methionine is generated,
SAM can be synthesized from the methionine, as indicated in the figure below.
Pathway showing the metabolism of major amino acids into acetyl-CoA and citric acid
cycle intermediate molecules. Genetic deficiencies can cause dysfunction of parts of
the pathway, leading to specific pathologies.

Cobalamin (choice B) levels are not affected by folate levels. Cobalamin is a vitamin
(vitamin B12) that is obtained from the diet, and increasing folate levels in cells will not
alter the amount of cobalamin present in cells.
Cystathionine (choice C) is an intermediate in cysteine synthesis that is derived from
homocysteine. The levels of cystathionine are limited by cysteine levels, such that when
cysteine levels are high, homocysteine is no longer sent down the pathway to cysteine
synthesis, which allows homocysteine to accumulate in a folate deficiency. Once folate
is given to the patient, homocysteine levels will drop, but the cystathionine levels will
remain largely unchanged.
Methionine (choice E) is incorrect because methionine levels will increase once folate
is given back to the patient (homocysteine can now be converted to methionine once
the levels of N5-methyltetrahydrofolate are brought to normal).

ReKap
 Genomic imprinting means that the expression of a gene depends on the sex of the parent
donating the gene.
 Prader-Willi syndrome usually arises due to the loss of the paternal copy of a segment of
chromosome 15 that is normally silenced in the homologous region on the maternal
chromosome. Classic features include hyperphagia, obesity, and intellectual disability.
 Angelman syndrome is usually due to a loss of a segment of a maternally transmitted
chromosome 15 that is normally silenced in the homologous region on the paternal
chromosome. Typical features include severe intellectual disability, happy disposition,
and puppet-like posture of the limbs.
 Other examples of sex differences in genetic transmission are X-linked recessive or
dominant, mitochondrial, or Y-linked inheritance.
Analysis
The correct answer is A. Genomic imprinting refers to the differential expression
of genes inherited from the father and the mother. Imprinting is a genomic
“silencing” in which genes on the maternal chromosome are not expressed (maternal
imprinting) or genes on the paternal chromosome are not expressed (paternal
imprinting).
If a defect occurs on the paternal chromosome in a gene that is maternally imprinted,
then the offspring will express the defective gene and be at risk to show the disease.
For example, Prader-Willi syndrome results from a deletion at a specific gene locus
on the paternally derived chromosome 15 that is imprinted on the maternally derived
chromosome 15.
Interestingly, a deletion of a paternally imprinted gene in the same locus in the
maternally derived chromosome 15 results in Angelman syndrome. This difference
reflects the fact that the genes deleted in Prader-Willi syndrome are normally active
only on the paternally transmitted chromosome, whereas the genes whose deletion
cause Angelman syndrome are normally active only on the maternally transmitted
chromosome.
In mitochondrial inheritance (choice B), only an affected mother can transmit the
disease phenotype; the offspring of affected males are always unaffected.
The other modes of inheritance would influence the relative proportions of affected
individuals who belong to one sex or the other:
Sex-dependent penetrance (choice C) occurs when there is differential penetrance
depending on sex.
X-linked recessive inheritance (choice D) will show a disproportionate number of
males affected irrespective of the father’s genotype.
Y-linked inheritance (choice E) would be expected to only affect males, with no
transmission from father to daughters.
During an investigational study of pyruvate dehydrogenase activity under different conditions,

two muscle needle biopsy specimens are obtained from the quadriceps. The first is taken from a
healthy volunteer at rest; the second is taken after the volunteer performs 30 minutes of aerobic
exercise on a stationary bicycle. The mitochondria from each biopsy sample are isolated and the
metabolic contents of the mitochondria are determined by various spectroscopic techniques.
Mitochondria from the exercising muscle show increased pyruvate dehydrogenase (PDH)
activity compared with the control. Which one of the following changes most likely allows for
increased PDH activity in the exercising muscle?
ReKap
 The pyruvate dehydrogenase (PDH) complex decarboxylates pyruvate from glycolysis to

CO2 and acetyl CoA as NAD+ is reduced to NADH.
 The PDH complex is active if dephosphorylated by PDH phosphatase and inactive if
phosphorylated by PDH kinase.
 The kinase and phosphatase are regulated allosterically. The kinase is inhibited by
pyruvate and ADP and activated by acetyl CoA, NADH, and ATP. The phosphatase is
activated by calcium.
 Increased activity of PDH is necessary to break down the large amounts of pyruvate built
up in the muscle from glycolysis and to use the product of that breakdown (acetyl-CoA)
in the citric acid cycle to generate energy.
Analysis
The correct answer is E. Mitochondrial PDH activity is increased by increasing
pyruvate (substrate) levels.
The PDH complex links glycolysis and the citric acid cycle. PDH catalyzes an
oxidative decarboxylation reaction in that it decarboxylates pyruvate (the end product of
glycolysis) with the production of NADH and acetyl-CoA (the substrate for the citric acid
cycle). This relationship is shown in the figure below.
The PDH complex is composed of many copies of at least five separate enzymes and is
highly regulated:
 Pyruvate decarboxylase, dihydrolipoyl transacetylase, and dihydrolipoyl

dehydrogenase catalyze the biochemical reactions.
 PDH kinase and PDH phosphatase covalently regulate the complex.
 Phosphorylation by PDH kinase → ↓ PDH activity.
 Dephosphorylation by PDH phosphatase → ↑ PDH activity.
 PDH kinase and PDH phosphatase are themselves regulated allosterically.
 Acetyl CoA and NADH, the products of the PDH reaction, activate PDH kinase
(which leads to inactivation of the PDH).
 High ADP and pyruvate concentrations inhibit PDH kinase.
 ↑ Ca2+ stimulates PDH phosphatase.
 Both effects produce more of the dephosphorylated, more active form of the PDH
complex.
PDH deficiency leads to lactic acidosis, neurological deficits, hypotonia,
and failure to thrive.
Decreased ADP levels (choice A) would reduce PDH activity, not increase it. During
exercise, ADP levels increase, which inhibits PDH kinase. PDH activity then increases
following dephosphorylation by PDH phosphatase.
Intracellular calcium and mitochondrial calcium are increased, not decreased (choice
B), with exercise. Calcium increases PDH activity by activating PDH phosphatase.
Increased acetyl-CoA (choice C), a product of the PDH complex, decreases PDH
activity by activating PDH kinase. In aerobic conditions, the acetyl-CoA would be further
consumed in the citric acid cycle. Acetyl-CoA is also an allosteric inhibitor of the PDH
complex itself.
Increased NADH/NAD+ (choice D), as is seen when the cell's need for reduced NADH is
already being adequately met, decreases PDH activity by activating PDH kinase. In
aerobic conditions, the NADH would be re-oxidized to NAD +, producing ATP in
oxidative phosphorylation.

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Hereditary hemochromatosis exhibits an autosomal recessive inheritance pattern.

Hardy-Weinberg equilibrium formula: p2 + 2pq +q2 = 1.

 p = frequency of allele 1 (normal allele).

Weinberg equilibrium (HWE) rule (p2 + 2pq +q2 = 1), where

matings, focus on the gametes in the population as a whole. We know that the man

is (0.5) x (0.1) = (0.05).

 Consanguinity increases the incidence of any autosomal recessive condition.

The 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

the disorder appears to be hereditary and that it is not X-linked, because there is no

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 of glucose 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

normal plasma membrane Na+–K+ ATPase activity, secondarily causing swelling and

may not produce symptoms later in life. Increased concentrations of glycolytic

bisphosphoglycerate (2,3-BPG) in red cells are present, leading to a lower affinity of

jaundice, and splenomegaly (extravascular hemolysis). Echinocytes would be observed

on the peripheral blood smear.

Debranching enzyme (α-1,4, α-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

make that gene defect unlikely.

Deficiency of muscle phosphorylase (myophosphorylase; choice D) produces

 Glucose 6-phosphatase deficiency (Von Gierke disease) is an autosomal recessive

pronounced hepatomegaly. Hepatomegaly and hypoglycemic seizures strongly

suggest a glycogen storage disease (GSD).

Three of the enzymes listed are related to glycogen storage diseases:

 Acid maltase (choice A; also called lysosomal α1,4-glucosidase; deficiency results in

glucose-6-phosphatase (GSD type Ia) or of glucose-6-phosphate translocase (GSD

type Ib). It typically presents between 3-4 months of age with hypoglycemia,

seizures may occur during episodes of profound hypoglycemia. The glycogen

accumulation in von Gierke disease occurs primarily in the liver and kidneys,

derangement of glucose metabolism. Due to allelic heterogeneity, the onset of

Pompe disease (choice A) is a muscle glycogenolysis disorder associated with skeletal

and cardiac muscle involvement. The primary symptom in Pompe disease is severe

cardiomegaly. McArdle disease (choice E) is also a muscle glycogenolysis

manifesting with relatively mild symptoms (muscle cramps and weakness on

exercise, myoglobinuria). It causes muscle weakness beginning in the second or third

decade of life and no hepatomegaly, so this option can be excluded.

Beta-glucocerebrosidase deficiency (choice B) causes Gaucher disease, a lysosomal

storage disease, which is characterized by hepatosplenomegaly and glucocerebroside

accumulation in phagocytic cells.

Hexosaminidase A (choice D) deficiency is associated with Tay-Sachs disease, a

lysosomal storage disease, which is characterized by progressive neurologic

deterioration. Cherry-red spots in the macular region precede blindness. Note that

The table below summarizes the glycogen storage diseases.

Type Deficient Cardinal Clinical Glycogen

The correct answer is C. In addition to the well-known intellectual disabilities

associated with Down syndrome (trisomy 21), affected individuals have an increased

incidence of a variety of medical problems. Acute myeloblastic leukemia (AML) is

seen in newborns and acute lymphoblastic leukemia (ALL) is seen in older