Inherited Metabolic And Single-Gene Disorders
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USMLE Step 1 › Inherited Metabolic And Single-Gene Disorders
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?
Observe without intervention until developmental delays appear
Begin dietary phenylalanine restriction with tyrosine supplementation immediately
Start levodopa-carbidopa to replace deficient catecholamines
Administer intravenous glucose to suppress amino acid catabolism
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.
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?
Autoantibody-mediated hemolysis leading to episodic complement activation
Reduced heme synthesis causing microcytosis and ineffective erythropoiesis
Defective spectrin causing membrane fragility and spherocytosis
Polymerization of deoxygenated hemoglobin S leading to red cell sickling and vaso-occlusion
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.
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?
Deletion of HEXA promoter increasing hexosaminidase A expression
Trinucleotide repeat expansion in CFTR altering chloride conductance
Loss-of-function variants in PAH reducing phenylalanine hydroxylase activity
Gain-of-function variants in HBB increasing hemoglobin oxygen affinity
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 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.
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?
X-linked recessive with lyonization in females
Autosomal recessive with codominant expression at the protein level
Mitochondrial inheritance with maternal transmission
Autosomal dominant with variable penetrance
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.
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?
Inability to convert tyrosine to melanin leading to progressive demyelination
Defective urea cycle leading to hyperammonemia and cerebral edema
Impaired conversion of phenylalanine to tyrosine leading to neurotoxic metabolite accumulation
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.