WBR0089

Author	[[PageAuthor::Ogheneochuko Ajari, MB.BS, MS [1] (Reviewed by Will Gibson, Jad Al Danaf, Rim Halaby, M.D. [2])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry, MainCategory::Genetics
Sub Category	SubCategory::Neurology
Prompt	[[Prompt::A 46-year-old man is brought to the emergency department by his son for worsening jerky movements, progressive loss of memory and aggressiveness. His symptoms began 2 years ago and have progressively worsened. The patient's father and grandfather died of similar symptoms. Deficiency of which of the following is most likely responsible for this patient's symptoms?]]
Answer A	AnswerA::Serotonin
Answer A Explanation	[[AnswerAExp::Serotonin is decreased in anxiety, depression and increased in Parkinson’s disease]]
Answer B	AnswerB::GABA
Answer B Explanation	[[AnswerBExp::Patients with Huntington's disease have a deficiency of the neurotransmitters GABA and acetylcholine.]]
Answer C	AnswerC::Dopamine
Answer C Explanation	[[AnswerCExp::Dopamine is increased in schizophrenia, but decreased in Parkinson’s disease and depression. It is not known to be altered in Huntington's disease.]]
Answer D	AnswerD::Glutamate
Answer D Explanation	[[AnswerDExp::Glutamate is used by the brain to synthesize GABA but its deficiency is not implicated in the pathogenesis of Huntington's disease. Instead, neurons are thought to undergo "excitotoxic death" in Huntington disease, whereby mutant huntingtin protein increases glutamatergic neurotransmission through NMDA receptors to neurotoxic levels.]]
Answer E	AnswerE::Norepinephrine
Answer E Explanation	[[AnswerEExp::Norepinephrine is a neurotransmitter that is increased in anxiety and decreased in depression.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::The patient in this vignette has Huntington’s disease, a uniformly fatal neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline. Symptoms manifest in affected individuals between the ages of 20 and 50. Clinical findings include depression, progressive dementia, choreiform movements, caudate atrophy and decreased levels of both GABA and acetylcholine in the brain. It is a trinucleotide repeat disorder caused by (CAG)n repeats in the Huntingtin gene located on chromosome 4. Expansion of this CAG triplet repeat stretch within the Huntingtin gene results in a different (mutant) form of the protein that gradually damages cells in the brain through mechanisms that are not fully understood. The disease is inherited in an autosomal dominant manner and displays genetic anticipation. This anticipation is thought to be caused by polymerase "slippage" during DNA replication in germ cells, thereby increasing the length of the repeat segment. The common neuropathology in Huntington's disease occurs within the neostriatum, in which gross atrophy of the caudate and putamen nuclei occurs and accompanied by selective neuronal loss and astrogliosis. Wiki-mnemomic: You hunt animals and put them in the CAGe: Huntington Disease is a CAG repeat disorder. Educational Objective: Huntington's disease is associated with a deficiency of GABA and acetylcholine in the brains of affected patients. Huntington's disease is the most common genetic cause of abnormal involuntary movements called chorea, which is why the disease used to be called Huntington's chorea. References: First Aid 2014 page 454]]
Approved	Approved::Yes
Keyword	WBRKeyword::Brain, WBRKeyword::Neurodegenerative, WBRKeyword::Huntington disease, WBRKeyword::Huntington's disease, WBRKeyword::Genetics, WBRKeyword::Neurology, WBRKeyword::Neurotransmitter, WBRKeyword::Depression, WBRKeyword::GABA, WBRKeyword::Acetylcholine
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