WBR0646

Author	[[PageAuthor::Rim Halaby, M.D. [1]]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::Dermatology, SubCategory::General Principles
Prompt	[[Prompt::A 6 year old boy who has not been followed up at a pediatrics clinic presents for 3 days of high grade fever. Examination reveals pharyngeal exudates, but the physician notices something unusual. The child had several bruises on his arms and legs which his mother explains have been there on and off since the child was born. Further examination reveals hyperextensibile skin, and cigarette paper like scars on both knees. The physician suspects a genetic disease and sends blood samples for analysis. Two weeks later, results of the genetic testing show a mutation in the COL5A1 gene. Which of the following steps in collagen synthesis is likely to be defective in this patient? ]]
Answer A	AnswerA::A
Answer A Explanation	AnswerAExp::This step refers to the hydroxylation of proline and lysine residues mediated by Vitamin C. Scurvy would lead to a defect in this phase of collagen synthesis. It is not affected in Ehlers-Danlos syndrome.
Answer B	AnswerB::B
Answer B Explanation	AnswerBExp::This step refers to glycosylation of specific residues in the collagen chain. It is not affected in Ehlers-Danlos syndrome.
Answer C	AnswerC::C
Answer C Explanation	AnswerCExp::This step refers to collagen triple helix (procollagen) formation. It is defective in osteogenesis imperfecta. It is not affected in Ehlers-Danlos syndrome.
Answer D	AnswerD::D
Answer D Explanation	AnswerDExp::This step refers to the cleavage of the terminal regions of procollagen. It is not affected in Ehlers-Danlos syndrome.
Answer E	AnswerE::E
Answer E Explanation	AnswerEExp::This refers to collagen cross-linking via lysyl-oxidase (requires copper). This step is the defective step in Ehlers-Danlos disease.
Right Answer	RightAnswer::E
Explanation	[[Explanation::Ehlers-Danlos Syndrome is a rare inherited disease that is heterogeneous in presentation and pathologic mechanisms. Six subtypes of Ehlers-Danlos exist with each having distinct mutations affecting collagen synthesis. The classical types of Ehlers-Danlos involve mostly collagen type 1 and collagen type 4. One of the most studied pathological mechanisms of Ehlers-Danlos is a mutation affecting lysyl-oxidase, an enzyme responsible for collagen crosslinking in the extracellular matrix. Ehlers-Danlos classically presents with skin hyperextensibility, cutaneous fragility, joint hypermobility, and vascular anomalies. Physical exam also showns poor wound healing with "fish mouth" re-opened scars, or classic "cigarette paper" like scars which are poorly healed thin and fragile skin. The most dangerous subtype involves type 4 collagen and leads to increased risk of visceral perforation and arterial rupture. Mutations often involve the COL-A genes. Learning objective: Ehlers-Danlos is a rare inherited disorder with certain forms characterized by defective corss-linking of collagen fibers. Reference: Wenstrup RJ, Florer JB, Willing MC, et al. COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet. 2000;66(6):1766-76. Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest. 2001;107(9):1063-9. Educational Objective: References: ]]
Approved	Approved::No
Keyword	WBRKeyword::Ehlers-Danlos Syndrome, WBRKeyword::Collagen sythesis, WBRKeyword::Lysyl oxidase
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::