USMLE PRACTICE QUESTION #124
TOPIC: Genetics/Pathology
USMLE practice question #124 will test your understanding of a commonly tested genetics condition.
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A 38-year-old man presents to the clinic with progressive mood changes, difficulty with coordination, and recent episodes of involuntary, jerking movements involving his upper and lower extremities. His family notes that he has become increasingly irritable and has difficulty with memory and decision-making. Physical examination reveals generalized chorea and impaired rapid alternating movements. MRI of the brain shows bilateral caudate nucleus atrophy. Which of the following changes in neurotransmitter activity is most likely contributing to this patient’s condition?
A) Increased GABAergic signaling in the basal ganglia
B) Increased dopamine activity in the nigrostriatal pathway
C) Decreased glutamate activity in the thalamus
D) Decreased GABAergic signaling in the striatum
E) Decreased acetylcholine activity in the cerebral cortex
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following changes in neurotransmitter activity is most likely contributing to this patient’s condition?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Identify the condition; 2nd: Identify the neurotransmitter change(s).
Step 3: Read the vignette carefully and ask yourself: “Based on my diagnosis, the alteration in neurotransmitter activity is _________________________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 38-year-old man presents with progressive mood changes, cognitive decline, involuntary movements (chorea), and difficulty with coordination, along with MRI findings of bilateral caudate nucleus atrophy. These findings are classic for Huntington's disease (HD), a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4.
ANSWER CHOICES:
CHOICE A: Increased GABAergic signaling in the basal ganglia
Explanation: GABA is the primary inhibitory neurotransmitter in the basal ganglia. Increased GABAergic signaling would lead to hypokinetic movement disorders (e.g., Parkinson's disease) rather than hyperkinetic disorders like chorea.
CHOICE B: Increased dopamine activity in the nigrostriatal pathway
Explanation: Dopamine modulates motor activity through its effects on the direct and indirect pathways of the basal ganglia. Increased dopamine activity can exacerbate hyperkinetic symptoms but is not the primary mechanism in HD.
CHOICE C: Decreased glutamate activity in the thalamus
Explanation: Glutamate is an excitatory neurotransmitter that plays a role in thalamocortical communication. Decreased glutamate activity would impair motor output, leading to hypokinesia rather than hyperkinesia.
CHOICE D: Decreased GABAergic signaling in the striatum
Explanation: Medium spiny neurons (MSNs) in the striatum are GABAergic and are preferentially affected in Huntington's disease. Loss of these neurons leads to decreased inhibition of the globus pallidus externa (GPe) via the indirect pathway, resulting in disinhibition of the thalamus and excessive excitatory output to the cortex.
CHOICE E: Decreased acetylcholine activity in the cerebral cortex
Explanation: Acetylcholine plays a role in cortical and subcortical communication, but its dysfunction is not central to Huntington's disease pathophysiology.
FINAL VERDICT…
CORRECT ANSWER: D) Decreased GABAergic signaling in the striatum
The hallmark pathophysiological feature of Huntington's disease is selective degeneration of medium spiny neurons (MSNs) in the striatum, leading to decreased GABAergic inhibition within the indirect pathway of the basal ganglia. This results in disinhibition of thalamocortical circuits, causing hyperkinetic movements such as chorea.
KEY CONCEPTS:
Huntington's Disease Overview:
Caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4.
Characterized by motor (chorea), cognitive (memory loss, executive dysfunction), and psychiatric (irritability, depression) symptoms.
Neuropathology:
Atrophy of the caudate nucleus and putamen (striatum).
Loss of medium spiny neurons (MSNs), particularly those involved in the indirect pathway.
Pathophysiology:
Decreased GABAergic signaling from MSNs leads to disinhibition of thalamocortical circuits via reduced inhibition of the globus pallidus externa (GPe).
Results in excessive excitatory output to motor areas of the cortex, causing hyperkinetic movements.
Clinical Features:
Early symptoms include subtle mood changes and cognitive decline.
Motor symptoms progress from chorea to dystonia and bradykinesia as disease advances.
Imaging Findings:
MRI shows atrophy of the caudate nucleus and dilation of lateral ventricles.
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