- This patient's disorder is caused by a deficiency of which of the following enzymes?
Answer: Glucocerebrosidase
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.
- This patient's condition is most likely caused by which of the following?
Answer: A reduced number of functional cell-surface LDL receptors
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.
- The genetic mutation responsible for this patient's condition most likely involves which of the following mechanisms?
Answer: An expansion of a CAG trinucleotide repeat
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.
- 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?
Answer: Impaired conversion of phenylalanine to tyrosine leading to neurotoxic metabolite accumulation
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.
- A deficiency of which of the following enzymes is responsible for this syndrome?
Answer: Hypoxanthine-guanine phosphoribosyltransferase
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.
- 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?
Answer: Polymerization of deoxygenated hemoglobin S leading to red cell sickling and vaso-occlusion
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.
- The specific mutation responsible for this patient's disease results in which of the following amino acid substitutions?
Answer: Valine replaces glutamic acid at the sixth position
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.
- This patient's condition is most likely caused by a defect in the synthesis or structure of which of the following?
Answer: Type I collagen
The triad of multiple fractures with minimal trauma, blue sclerae, and hearing loss is classic for osteogenesis imperfecta (OI), also known as brittle bone disease. Most cases of OI are autosomal dominant and result from mutations in the COL1A1 or COL1A2 genes, which code for the alpha chains of type I collagen. Type I collagen is the primary structural protein in bone, skin, tendons, and sclera. Defective collagen leads to bone fragility. The blue sclerae are due to the translucency of the thin sclera, allowing the underlying choroidal veins to be seen.
- A mutation in the gene coding for which of the following proteins is the most likely cause of this patient's syndrome?
Answer: Fibrillin-1
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.
- This disorder is characterized by the lysosomal accumulation of which of the following substances?
Answer: GM2 ganglioside
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.
- The protein product of the mutated gene in this patient's disorder normally functions to do which of the following?
Answer: Accelerate the inactivation of Ras proteins
The patient's features (café-au-lait spots, axillary freckling, cutaneous neurofibromas, and Lisch nodules) are diagnostic of Neurofibromatosis type 1 (NF1), an autosomal dominant disorder. The NF1 gene encodes neurofibromin, a tumor suppressor protein that acts as a GTPase-activating protein (GAP). It accelerates the conversion of active Ras-GTP to inactive Ras-GDP, thereby downregulating the Ras signal transduction pathway and controlling cell proliferation.
- This patient's condition is most likely caused by a mutation in the gene encoding which of the following proteins?
Answer: Dystrophin
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.
- 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?
Answer: Begin dietary phenylalanine restriction with tyrosine supplementation immediately
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.
- This patient's metabolic derangements are due to a hereditary deficiency of which of the following enzymes?
Answer: Glucose-6-phosphatase
This clinical presentation is classic for Von Gierke disease (Glycogen Storage Disease Type I). It is caused by a deficiency of glucose-6-phosphatase, an enzyme primarily found in the liver and kidneys that is required for the final step of both gluconeogenesis and glycogenolysis. Its absence leads to severe fasting hypoglycemia, hepatomegaly (due to glycogen accumulation), lactic acidosis, hyperuricemia, and hyperlipidemia.
- This patient's acute hemolytic episode was most likely precipitated by oxidative stress in the setting of which underlying enzyme deficiency?
Answer: Glucose-6-phosphate dehydrogenase
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.
- The genetic abnormality underlying this patient's condition is best described as which of the following?
Answer: An expansion of a CGG trinucleotide repeat in a noncoding region
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.
- 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?
Answer: Autosomal recessive with codominant expression at the protein level
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.
- A deficiency of which of the following coagulation factors is the most likely cause of this boy's condition?
Answer: Factor VIII
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.
- A 36-hour-old newborn girl has phenylalanine flagged on state newborn screening. She is asymptomatic. Confirmatory plasma amino acids show phenylalanine 20 mg/dL and low tyrosine. Urine shows phenylketones. PAH sequencing confirms biallelic pathogenic variants. The family asks which mutation category best fits the typical cause. Which of the following is the most likely genetic mutation?
Answer: Loss-of-function variants in PAH reducing phenylalanine hydroxylase activity
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 screening, which is indicative of phenylketonuria. The correct choice is A because it accurately explains the genetic mutation involved, leading to reduced enzyme activity. A common distractor is B which is incorrect because it describes a gain-of-function not seen in PKU. 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.
- The primary molecular defect in this patient's condition results from which of the following?
Answer: Improper protein folding and degradation of a transmembrane ion channel
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.
