WBR0369

Author	[[PageAuthor::Serge Korjian, M.D., Gonzalo A. Romero, M.D. [1](Reviewed by Serge Korjian)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry, MainCategory::Pathology, MainCategory::Pathophysiology
Sub Category	SubCategory::Neurology
Prompt	[[Prompt::A research lab develops a new knock-in mouse model with a chimeric mouse/human exon containing 140 CAG repeats inserted into a gene on the short arm of chromosome 4. The mice are grown and observed for a total 18 months. All mice develop increased locomotor activity and abnormal posturing at approximately 1 month of age, followed by hypoactivity at 4 months and gait abnormalities at 1 year. Which of the following neurochemical changes is associated with this syndrome?]]
Answer A	AnswerA::Decreased norepinephrine, Decreased serotonin, Decreased dopamine
Answer A Explanation	AnswerAExp::This combination of neurotransmitter disturbances is associated with depression. Dopamine is mildly elevated in patients with Huntington's disease.
Answer B	AnswerB::Increased norepinephrine, Increased serotonin, Increased dopamine
Answer B Explanation	[[AnswerBExp::This combination of neurotransmitter disturbances is associated with schizophrenia. Increased dopamine is hypothesized to be the main cause of positive symptoms of schizophrenia. This is further validated by the significant effect of antipsychotics, or dopamine antagonists, on positive symptoms.]]
Answer C	AnswerC::Increased acetylcholine, Increased serotonin, Decreased dopamine
Answer C Explanation	AnswerCExp::This combination of neurotransmitter disturbances is associated with Parkinson's disease.
Answer D	AnswerD::Decreased GABA, Decreased acetylcholine, Increased dopamine
Answer D Explanation	AnswerDExp::Decreased GABA and acetylcholine, and increased dopamine are characteristic findings in Huntington's disease and are related to caudatal atrophy.
Answer E	AnswerE::Increased norepinephrine, Decreased GABA, Decreased serotonin
Answer E Explanation	AnswerEExp::This combination of neurotransmitter disturbances may be observed in patients with generalized anxiety disorder.
Right Answer	RightAnswer::D
Explanation	[[Explanation::The mouse model presented is an experimental approach for the investigation of Huntington's disease. The disorder has an autosomal dominant inheritance with the HD gene (huntingtin protein) on chromosome 4p harboring an expansion of the CAG repeats. While healthy individuals may have up to 35 repeats, patients with Huntington's disease have 36 or more repeats. Patients initially present with personality alterations, mood disorders (commonly depression), and aggressiveness. This is later followed by dystonic posturing and rigidity, choreiform movements, and dementia. Huntington's disease is often used as a classical example of anticipation i.e. earlier manifestation of the disease due to further expansion of the CAG repeats in subsequent affected generations. A classical finding in these patients is atrophy of the caudate nucleus which is often evident on brain imaging. Atrophy of the caudate leads to decreased GABA and acetylcholine, with increased dopamine due to disrupted dopaminergic regulation in the basal ganglia. The disordered neurotransmitter balance is responsible for the characteristic symptoms of chorea and mood changes. Educational Objective: Huntington's disease is an autosomal dominant disorder caused by a CAG trinucleotide expansion in the HD gene on chromosome 4p. It is characterized by caudate atrophy leading to a decrease in GABA and acetylcholine, and an increase in dopamine. References: First Aid 2013 page 461 Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet MF. Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats. J Comp Neurol. 2003;465(1):11-26. Crow TJ, Baker HF, Cross AJ, et al. Monoamine mechanisms in chronic schizophrenia: post-mortem neurochemical findings. Br J Psychiatry. 1979;134:249-56.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Huntington's disease, WBRKeyword::GABA, WBRKeyword::Serotonin, WBRKeyword::CAG, WBRKeyword::Trinucleotide repeat disorders, WBRKeyword::caudate
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