All questions
Question 1
A term newborn girl has an abnormal state newborn screen with phenylalanine 18 mg/dL (normal <2) and an elevated phenylalanine-to-tyrosine ratio. She is feeding well and appears normal on exam. Pregnancy is uncomplicated, and the mother denies alcohol or drug use. Family history is notable for a cousin with intellectual disability of unclear cause. Confirmatory plasma amino acids show markedly elevated phenylalanine with low tyrosine. Urine organic acids show increased phenylpyruvate. Genetic testing identifies biallelic pathogenic variants in the PAH gene. The parents ask what should be done now to prevent neurologic injury. What is the most appropriate next step in management?
- Begin dietary phenylalanine restriction with tyrosine supplementation immediately (correct answer)
- Start levodopa-carbidopa to replace deficient catecholamines
- Administer intravenous glucose to suppress amino acid catabolism
- Observe without intervention until developmental delays appear
Explanation: This question tests understanding of inherited metabolic and single-gene disorders. These disorders often result from specific genetic mutations affecting metabolic pathways. In this vignette, the patient presents with elevated phenylalanine on newborn screen, which is indicative of phenylketonuria. The correct choice is A because it accurately explains the genetic mutation involved, leading to prevention of neurologic injury through diet. A common distractor is D which is incorrect because waiting for symptoms risks irreversible damage. Teaching strategies: Encourage students to focus on recognizing patterns in genetic mutations and their biochemical consequences. Practice with case studies to reinforce understanding of inheritance patterns and clinical presentations.
Question 2
A 15-year-old boy with a history of intermittent severe limb and back pain presents with acute chest pain and shortness of breath after a viral illness. He has pallor, scleral icterus, and mild splenomegaly. Labs show hemoglobin 7.8 g/dL, reticulocyte count 9%, elevated lactate dehydrogenase, and indirect hyperbilirubinemia. Peripheral smear shows sickled erythrocytes and target cells. Hemoglobin electrophoresis shows 92% hemoglobin S, 6% hemoglobin F, and no hemoglobin A. His parents are asymptomatic; one sibling has “trait.” Genetic testing confirms a homozygous missense variant in the HBB gene. The family asks how this disorder is transmitted and why carriers are usually asymptomatic. What is the inheritance pattern of this disorder?
- Autosomal dominant with variable penetrance
- Autosomal recessive with codominant expression at the protein level (correct answer)
- X-linked recessive with lyonization in females
- Mitochondrial inheritance with maternal transmission
Explanation: This question tests understanding of inherited metabolic and single-gene disorders. These disorders often result from specific genetic mutations affecting metabolic pathways. In this vignette, the patient presents with acute chest pain, anemia, and sickled erythrocytes, which is indicative of sickle cell disease. The correct choice is B because it accurately explains the genetic mutation involved, leading to codominant expression where carriers are asymptomatic but homozygotes have disease. A common distractor is A which is incorrect because sickle cell is recessive, not dominant with variable penetrance. Teaching strategies: Encourage students to focus on recognizing patterns in genetic mutations and their biochemical consequences. Practice with case studies to reinforce understanding of inheritance patterns and clinical presentations.
Question 3
A 5-day-old boy has a positive newborn screen showing elevated phenylalanine. He is born at term and appears well. Confirmatory testing shows phenylalanine 22 mg/dL, low tyrosine, and increased phenylpyruvate in urine. Genetic testing demonstrates biallelic pathogenic variants in PAH. The parents ask why untreated disease causes intellectual disability and seizures. Which of the following best explains the pathophysiology of this condition?
- Impaired conversion of phenylalanine to tyrosine leading to neurotoxic metabolite accumulation (correct answer)
- Inability to convert tyrosine to melanin leading to progressive demyelination
- Defective urea cycle leading to hyperammonemia and cerebral edema
- Defective glycogen breakdown leading to hypoglycemia and lactic acidosis
Explanation: This question tests understanding of inherited metabolic and single-gene disorders. These disorders often result from specific genetic mutations affecting metabolic pathways. In this vignette, the patient presents with elevated phenylalanine and low tyrosine, which is indicative of phenylketonuria. The correct choice is A because it accurately explains the genetic mutation involved, leading to neurotoxic buildup. A common distractor is B which is incorrect because it confuses with albinism or other tyrosine defects. Teaching strategies: Encourage students to focus on recognizing patterns in genetic mutations and their biochemical consequences. Practice with case studies to reinforce understanding of inheritance patterns and clinical presentations.
Question 4
A 16-year-old boy with sickle cell disease presents for routine follow-up. He has a history of dactylitis as an infant and multiple vaso-occlusive crises. Exam shows scleral icterus and a palpable spleen tip is absent. Labs show hemoglobin 8.9 g/dL, elevated reticulocyte count, and indirect hyperbilirubinemia. Hemoglobin electrophoresis shows predominantly hemoglobin S with increased hemoglobin F. He asks why hypoxia and dehydration trigger painful crises. Which of the following best explains the pathophysiology of this condition?
- Polymerization of deoxygenated hemoglobin S leading to red cell sickling and vaso-occlusion (correct answer)
- Autoantibody-mediated hemolysis leading to episodic complement activation
- Defective spectrin causing membrane fragility and spherocytosis
- Reduced heme synthesis causing microcytosis and ineffective erythropoiesis
Explanation: This question tests understanding of inherited metabolic and single-gene disorders. These disorders often result from specific genetic mutations affecting metabolic pathways. In this vignette, the patient presents with recurrent vaso-occlusive crises and anemia, which is indicative of sickle cell disease. The correct choice is A because it accurately explains the genetic mutation involved, leading to sickling under hypoxia. A common distractor is C which is incorrect because it describes hereditary spherocytosis. Teaching strategies: Encourage students to focus on recognizing patterns in genetic mutations and their biochemical consequences. Practice with case studies to reinforce understanding of inheritance patterns and clinical presentations.
Question 5
A 42-year-old man is brought to the neurologist by his wife due to progressive behavioral changes and abnormal movements over the past year. She reports he has become increasingly irritable, impulsive, and depressed. On examination, he exhibits random, involuntary, rapid movements of his face, trunk, and limbs. His father had a similar illness and died in a nursing home at age 55. An MRI of the brain shows atrophy of the caudate nucleus.
The genetic mutation responsible for this patient's condition most likely involves which of the following mechanisms?
- A frameshift mutation in a tumor suppressor gene
- An expansion of a CAG trinucleotide repeat (correct answer)
- A missense mutation in a gene encoding a structural protein
- A defect in a transmembrane chloride channel protein
Explanation: The patient's presentation of chorea, psychiatric disturbances, and a family history consistent with autosomal dominant inheritance is classic for Huntington disease. This neurodegenerative disorder is caused by an expansion of a CAG (cytosine-adenine-guanine) trinucleotide repeat in the huntingtin (HTT) gene, leading to a toxic gain-of-function protein. The atrophy of the caudate nucleus is a characteristic imaging finding.
Question 6
A newborn male develops meconium ileus shortly after birth, requiring surgical intervention. Over the next two years, he experiences recurrent respiratory infections with Pseudomonas aeruginosa and fails to gain weight despite a good appetite. A sweat chloride test is performed and is markedly elevated.
The primary molecular defect in this patient's condition results from which of the following?
- Deficiency of the enzyme phenylalanine hydroxylase
- Absence of the structural protein dystrophin in muscle cells
- Improper protein folding and degradation of a transmembrane ion channel (correct answer)
- Accumulation of GM2 ganglioside in neuronal lysosomes
Explanation: This patient's presentation of meconium ileus, recurrent pulmonary infections, and failure to thrive, along with an elevated sweat chloride test, is diagnostic of cystic fibrosis (CF). CF is an autosomal recessive disorder caused by mutations in the CFTR gene. The most common mutation (ΔF508) leads to misfolding of the CFTR protein, a chloride channel, which is then targeted for premature degradation in the proteasome, preventing its insertion into the cell membrane.
Question 7
A 16-year-old boy is evaluated for his tall stature during a pre-sports physical. He is in the 99th percentile for height. Physical examination reveals long, thin extremities with an arm span exceeding his height, pectus excavatum, and joint hypermobility. He also has significant myopia. An echocardiogram is ordered to screen for potential cardiovascular complications.
A mutation in the gene coding for which of the following proteins is the most likely cause of this patient's syndrome?
- Fibrillin-1 (correct answer)
- LDL receptor
- Neurofibromin
- Type IV collagen
Explanation: This patient's constellation of findings, including tall stature, arachnodactyly (long, thin extremities), pectus excavatum, and myopia, is classic for Marfan syndrome. This is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, which encodes fibrillin-1. Fibrillin-1 is a key component of microfibrils, which form the scaffold for elastic fibers. Aortic root dilation and dissection are major cardiovascular risks.
Question 8
A newborn screening test is positive for a metabolic disorder in a 2-day-old infant. The infant currently appears healthy, but if left untreated, is at high risk for severe intellectual disability, seizures, and a musty body odor. The parents are advised to start the infant on a special formula immediately.
To prevent the neurologic sequelae of this disorder, dietary intake of which of the following must be strictly limited?
- Galactose
- Leucine
- Phenylalanine (correct answer)
- Tyrosine
Explanation: The scenario describes phenylketonuria (PKU), an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase. This enzyme converts phenylalanine to tyrosine. Without it, phenylalanine accumulates and is converted to phenylketones, which are neurotoxic. The musty odor is due to these metabolites. Treatment involves lifelong dietary restriction of phenylalanine.
Question 9
A 24-year-old man of Mediterranean descent develops acute-onset jaundice, fatigue, and dark-colored urine. He states he recently attended a party where he ate fava beans. His medical history is otherwise unremarkable. Laboratory studies reveal a normocytic anemia, elevated indirect bilirubin, and increased lactate dehydrogenase. A peripheral blood smear shows red blood cells with bite cells and Heinz bodies.
This patient's acute hemolytic episode was most likely precipitated by oxidative stress in the setting of which underlying enzyme deficiency?
- Glucose-6-phosphate dehydrogenase (correct answer)
- Pyruvate kinase
- Aldolase B
- Glucocerebrosidase
Explanation: This is a classic presentation of G6PD deficiency, an X-linked recessive disorder. The enzyme G6PD is crucial for the pentose phosphate pathway, which produces NADPH. NADPH is necessary to keep glutathione reduced, protecting red blood cells from oxidative damage. Triggers like certain drugs (e.g., sulfonamides), infections, or fava beans cause oxidative stress, leading to hemolysis in deficient individuals. Heinz bodies are aggregates of denatured hemoglobin.
Question 10
A 40-year-old man presents for evaluation of small, yellowish nodules on his Achilles tendons and extensor tendons of his hands. He has a strong family history of premature coronary artery disease, with his father having died from a myocardial infarction at age 45. A fasting lipid panel reveals a total cholesterol level of 480 mg/dL and an LDL cholesterol level of 400 mg/dL.
This patient's condition is most likely caused by which of the following?
- Increased activity of HMG-CoA reductase
- Deficiency of lipoprotein lipase
- A reduced number of functional cell-surface LDL receptors (correct answer)
- A mutation in the apolipoprotein B-100 gene
Explanation: The presence of tendon xanthomas and markedly elevated LDL cholesterol in the context of a family history of premature cardiovascular disease is characteristic of familial hypercholesterolemia (FH). This autosomal dominant disorder is most commonly caused by mutations in the LDL receptor gene, leading to a decreased number of functional receptors on hepatocytes. This impairs the clearance of LDL from the circulation, resulting in severe hypercholesterolemia and accelerated atherosclerosis.
Question 11
A 9-month-old infant of Ashkenazi Jewish ancestry is brought to the pediatrician due to developmental regression. The parents report that the child, who was previously able to sit up, can no longer do so. On examination, the infant has decreased muscle tone, an exaggerated startle response to sound, and macrocephaly. Funduscopic examination reveals a cherry-red spot on the macula.
This disorder is characterized by the lysosomal accumulation of which of the following substances?
- GM2 ganglioside (correct answer)
- Glucocerebroside
- Sphingomyelin
- Heparan sulfate
Explanation: The clinical features—developmental regression, hypotonia, hyperacusis, cherry-red macula, and Ashkenazi Jewish heritage—are classic for Tay-Sachs disease. This is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme hexosaminidase A. This deficiency leads to the accumulation of its substrate, GM2 ganglioside, primarily in the neurons of the central nervous system, causing progressive neurodegeneration.
Question 12
A 50-year-old man presents with a 10-year history of progressive joint pain, primarily affecting his spine and knees. On physical examination, there is dark, bluish-black pigmentation of the sclerae and ear cartilage. He reports that his urine darkens and turns black if left to stand for several hours. X-rays of the spine show calcification of the intervertebral discs.
This patient's condition is caused by a deficiency in which of the following enzymes?
- Tyrosinase
- Homogentisate oxidase (correct answer)
- Branched-chain α-ketoacid dehydrogenase
- Cystathionine synthase
Explanation: This patient has alkaptonuria, a rare autosomal recessive disorder of tyrosine metabolism. It is caused by a deficiency of the enzyme homogentisate oxidase. This leads to the accumulation of homogentisic acid, which polymerizes into a dark pigment that deposits in connective tissues (ochronosis), causing the characteristic scleral and cartilage pigmentation and debilitating arthritis. The acid is also excreted in the urine, causing it to turn black upon oxidation.
Question 13
A 5-year-old boy is brought to the emergency department after falling from his bicycle. He has a large, swollen, and tender left knee. His mother reports that he has had several episodes of prolonged bleeding after minor cuts and that her brother also has a bleeding disorder. Coagulation studies show a normal prothrombin time (PT), a prolonged activated partial thromboplastin time (aPTT), and a normal bleeding time.
A deficiency of which of the following coagulation factors is the most likely cause of this boy's condition?
- Factor VII
- Factor VIII (correct answer)
- Factor X
- Factor II (Prothrombin)
Explanation: The clinical presentation of hemarthrosis after minor trauma, a family history consistent with X-linked recessive inheritance, and laboratory findings of an isolated prolonged aPTT are classic for Hemophilia A or B. Hemophilia A, the more common form, is caused by a deficiency of Factor VIII. Factor VIII is a component of the intrinsic coagulation pathway, which is assessed by the aPTT. The extrinsic (PT) and common pathways are unaffected.
Question 14
A 6-year-old boy is referred for neuropsychological testing due to learning disabilities and ADHD-like behaviors. His mother mentions that he has always been anxious in social situations. On physical examination, he has a long, narrow face, large, prominent ears, and a high-arched palate. Testicular examination reveals macroorchidism. His family history is notable for a maternal uncle with significant intellectual disability.
The genetic abnormality underlying this patient's condition is best described as which of the following?
- A deletion on the paternal copy of chromosome 15
- An expansion of a CGG trinucleotide repeat in a noncoding region (correct answer)
- Trisomy of chromosome 21
- A point mutation in the gene for fibrillin-1
Explanation: The combination of intellectual disability, characteristic physical features (long face, large ears, macroorchidism), and behavioral issues in a male suggests Fragile X syndrome. This is an X-linked dominant disorder and the most common inherited cause of intellectual disability. It is caused by an expansion of a CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene. This expansion leads to hypermethylation and silencing of the gene, resulting in a lack of the FMRP protein, which is vital for normal brain development.
Question 15
A 19-year-old African American woman with a known chronic hematologic condition presents with sudden onset of severe chest pain, cough, and shortness of breath. Her temperature is 38.5°C (101.3°F). A chest X-ray shows a new infiltrate in the right lower lobe. This condition is caused by a point mutation in the β-globin gene.
The specific mutation responsible for this patient's disease results in which of the following amino acid substitutions?
- Valine replaces glutamic acid at the sixth position (correct answer)
- Glutamic acid replaces valine at the sixth position
- Lysine replaces glutamic acid at the sixth position
- Alanine replaces glycine at the twelfth position
Explanation: The patient is presenting with acute chest syndrome, a common and serious complication of sickle cell disease. Sickle cell disease is an autosomal recessive disorder caused by a missense point mutation in the β-globin gene. This single nucleotide change (A to T) results in the substitution of a nonpolar valine for a polar glutamic acid at the sixth position of the β-globin chain. This change promotes the polymerization of deoxygenated hemoglobin (HbS), leading to red blood cell sickling, hemolysis, and vaso-occlusion.
Question 16
A 2-day-old male infant, born at term, develops progressive lethargy, vomiting, and poor feeding. On examination, he is tachypneic and hypotonic. Laboratory results show a plasma ammonia level of 1200 µmol/L (normal <50 µmol/L). Plasma glucose is normal. Urinalysis reveals markedly elevated orotic acid levels.
These findings are most consistent with a deficiency of which of the following enzymes?
- Carbamoyl phosphate synthetase I
- Arginase
- Ornithine transcarbamylase (correct answer)
- Aldolase B
Explanation: This infant has a urea cycle disorder, characterized by severe hyperammonemia. The combination of hyperammonemia and high urinary orotic acid is specific for ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder. It is an X-linked recessive condition. A block at OTC leads to the accumulation of its substrate, carbamoyl phosphate, which is shunted into the pyrimidine synthesis pathway, resulting in excessive production of orotic acid.
Question 17
A 25-year-old woman of Ashkenazi Jewish descent presents with chronic fatigue and a sensation of abdominal fullness. She also notes easy bruising and occasional bone pain in her femurs. Physical examination is significant for massive splenomegaly. A complete blood count reveals pancytopenia. A bone marrow aspirate shows large macrophages with abundant cytoplasm described as having a 'crinkled tissue paper' appearance.
This patient's disorder is caused by a deficiency of which of the following enzymes?
- Sphingomyelinase
- Glucocerebrosidase (correct answer)
- Hexosaminidase A
- Galactocerebrosidase
Explanation: The clinical presentation of hepatosplenomegaly, pancytopenia, and bone pain, along with the characteristic 'Gaucher cells' (macrophages with wrinkled tissue paper cytoplasm) on bone marrow biopsy, is diagnostic of Gaucher disease. This is the most common lysosomal storage disease, inherited in an autosomal recessive pattern. It is caused by a deficiency of the enzyme glucocerebrosidase (also called β-glucosidase), leading to the accumulation of glucocerebroside within the lysosomes of macrophages.
Question 18
A 4-year-old boy is brought to the pediatrician for evaluation of clumsiness. His parents report that he has difficulty running and climbing stairs and that he frequently falls. On physical examination, he is observed to use his hands to push off his thighs to stand up from a seated position. Marked enlargement of his calf muscles is noted. Serum creatine kinase levels are significantly elevated.
This patient's condition is most likely caused by a mutation in the gene encoding which of the following proteins?
- Fibrillin-1
- Type I collagen
- Spectrin
- Dystrophin (correct answer)
Explanation: The clinical picture of progressive proximal muscle weakness in a young boy, Gowers sign (using hands to stand), and calf pseudohypertrophy is characteristic of Duchenne muscular dystrophy (DMD). DMD is an X-linked recessive disorder caused by a frameshift or nonsense mutation in the gene encoding dystrophin, a large protein that links the intracellular cytoskeleton to the transmembrane dystroglycan complex in muscle cells.
Question 19
A 22-year-old man undergoes a screening colonoscopy due to a strong family history of early-onset colon cancer. His father and paternal aunt were both diagnosed in their late 30s. The procedure reveals over 500 adenomatous polyps carpeting the entire colon. Genetic testing is performed to confirm the diagnosis.
This patient most likely has an inherited germline mutation in which of the following types of genes?
- A proto-oncogene
- A DNA mismatch repair gene
- A tumor suppressor gene (correct answer)
- A tyrosine kinase receptor gene
Explanation: The finding of hundreds to thousands of adenomatous polyps in the colon is the hallmark of familial adenomatous polyposis (FAP), an autosomal dominant condition with nearly 100% penetrance for developing colorectal cancer if untreated. FAP is caused by a germline mutation in the APC (Adenomatous Polyposis Coli) gene. APC is a classic tumor suppressor gene. According to the two-hit hypothesis, individuals with FAP inherit one mutated allele ('first hit') in all their cells, and a sporadic mutation in the second allele ('second hit') in a colonic epithelial cell is sufficient to initiate polyp formation.
Question 20
A 3-year-old boy presents with intellectual disability, choreoathetoid movements, and a history of self-mutilating behavior, including biting his fingers and lips. His parents note orange-colored crystals in his diapers. Laboratory analysis reveals a high serum uric acid level.
A deficiency of which of the following enzymes is responsible for this syndrome?
- Adenosine deaminase
- Ornithine transcarbamylase
- Phenylalanine hydroxylase
- Hypoxanthine-guanine phosphoribosyltransferase (correct answer)
Explanation: This constellation of findings—intellectual disability, dystonia, self-mutilation, and hyperuricemia (causing orange urate crystals)—is pathognomonic for Lesch-Nyhan syndrome. This is an X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT is a key enzyme in the purine salvage pathway. Its deficiency leads to increased degradation of purines and overproduction of uric acid.