WBR0313

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Neurology
Prompt	[[Prompt::A 40-year-old man with Down syndrome is brought to his primary care physician by an employee of his assisted care facility for memory loss. The employee explains that the patient has always had baseline intellectual disability, but his condition has significantly worsened over the past year. He has increasingly forgotten where his room is and is unable to recognize staff he used to know well. Which of the following proteins is most likely responsible for predisposing the patient to his symptoms?]]
Answer A	AnswerA::Presenilin
Answer A Explanation	AnswerAExp::Mutations in the genes encoding presenilin 1 (chromosome 14) and presenilin 2 (chromosome 1) proteins cause early-onset forms of familial Alzheimer’s disease. However, presinilin mutations are not associated with Down syndrome.
Answer B	AnswerB::Apolipoprotein E
Answer B Explanation	[[AnswerBExp::The E4 variant of apolipoprotein E (chromosome 19) is a susceptibility factor that is associated with late-onset sporadic Alzheimer’s disease. Individuals who carry two APOE4 alleles have a 20-fold increased risk of Alzheimer’s disease compared with non-carriers. APOE allele status is not specifically related to Down syndrome.]]
Answer C	AnswerC::α-synuclein
Answer C Explanation	[[AnswerCExp::α-synuclein is a protein which aggregates intracellularly to form the Lewy bodies associated with Parkinson’s disease and dementia with Lewy bodies. Abnormalities of α-synuclein are not usually associated with Down syndrome.]]
Answer D	AnswerD::Tau
Answer D Explanation	[[AnswerDExp::Hyperphosphorylated tau composes the pathological neurofibrillary tangles which affects the brains of patients with Alzheimer’s disease. Although tau proteins are involved in the pathogenesis of the disease, they are not thought to be associated with the accelerated development of Alzheimer’s disease associated with Down Syndrome.]]
Answer E	AnswerE::Amyloid precursor protein
Answer E Explanation	AnswerEExp::An extra copy of the amyloid precursor protien (APP) on chromosome 21 is associated with the accelerated development of Alzheimer’s disease among patients with Down syndrome.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Patients with Down syndrome have a higher risk of developing early-onset Alzheimer’s disease. This increased risk is thought to be caused by an extra copy of the gene encoding the amyloid precursor protein (APP) on chromosome 21. The additional copy of the gene causes more APP protein to be synthesized. Eventually, APP is cleaved to generate β-amyloid (Aβ), and aggregates of β-amyloid compose the amyloid plaques, which are the pathological hallmark of Alzheimer’s disease. The processing of APP into β-amyloid is demonstrated in the figure below: Educational Objective: An extra copy of the amyloid precursor protien (APP) on chromosome 21 is associated with the accelerated development of Alzheimer’s disease among patients with Down syndrome. References: Cedazo-Minguez A, Cowburn RF. Apolipoprotein E: a major piece in the Alzheimer's disease puzzle. J Cell Mol Med. 2001;5(3):254-66. First Aid 2014 page 90, 483]]
Approved	Approved::Yes
Keyword	WBRKeyword::Down syndrome, WBRKeyword::Alzheimer's disease, WBRKeyword::Early-onset Alzheimer's disease, WBRKeyword::Apolipoprotein E, WBRKeyword::Chromosome 21
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