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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor={{Rim}}
|QuestionAuthor= {{SSK}} (Reviewed by Serge Korjian)
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Biochemistry
|MainCategory=Biochemistry
Line 8: Line 8:
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=Dermatology, General Principles
|SubCategory=Dermatology, General Principles
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
Line 20: Line 21:
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=Dermatology, General Principles
|SubCategory=Dermatology, General Principles
|Prompt=A 54 year old homeless, alcoholic man with history of multiple hospital admissions presents to the emergency room for 3 hours of increasing shortness of breath. On exam, the patient is afebrile, his pulse is 102 bpm, blood pressure is 143/89 mmHg, and respiratory rate is 24 breaths per minute. The ED physician notices several large bruises on the man's arms, legs, and anterior abdomen. Examination of the oral cavity reveals poor denition with severely swollen gums. The physician also notes 2 ulcers on the man's left sole which were reportedly there the last time the patient was admitted to the hospital 4 months ago. Which of the following steps in collagen synthesis is likely to be defective in this patient?
|Prompt=A 6-year-old boy with poor medical follow-up presents for 3 days of high grade fever. Physical examination initially reveals pharyngeal exudates, but the physician notices that the child displays several bruises on his arms and legs. The mother explains that the bruises have been appearing and disappearing spontaneously since the child was approximately 6 months old. 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?


[[Image:Collagen1.jpg|400px]]
[[Image:Collagen1.jpg|400px]]
|Explanation=Scurvy is a relatively rare disease occuring in patients with severe Vitamin C deficiency. As vitamin C is needed in the hydroxylation of proline and lysine residues during collagen synthesis, its deficiency would lead to signs and symptoms of collagen abnormality. Patients initially complain of nonspecific malaise and fatigue that would progress to bony pain and dyspnea. Physical exam would reveal multiple bruises compatible with easy bruisability due to decreased collagen synthesis in the skin. Other signs include swollen gums, poor wound healing, and anemia. Scurvy is usually seen only in patients with very poor nutrition since vitamin C is redundantly present in most diets. Treatment is usually restricted to vitamin C supplementation and supportive care.
|Explanation=Ehlers-Danlos Syndrome is a rare, inherited disorder that is heterogeneous in presentation and pathologic mechanisms. Six subtypes of Ehlers-Danlos exist 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: Vitamin C is important in the hydroxylation of proline and lysine residues during collagen synthesis. Vitamin C deficiency lead to scurvy characterized by ecchymoses, swollen gums, and poor wound healing.
 
 
Reference:
 
Kumar V, Abbas AK, Fausto N, Aster JC. Environmental and nutritional diseases. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Elsevier Saunders; 2009:chap 9.
|AnswerA=A
|AnswerA=A
|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.
|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.
|AnswerB=B
|AnswerB=B
|AnswerBExp=This step refers to glycosylation of specific residues in the collagen chain. It is not affected by vitamin C deficiency.
|AnswerBExp=This step refers to glycosylation of specific residues in the collagen chain. It is not affected in Ehlers-Danlos syndrome.
|AnswerC=C
|AnswerC=C
|AnswerCExp=This step refers to collagen triple helix (procollagen) formation. It is defective in osteogenesis imperfecta. It is not affected by vitamin C deficiency.
|AnswerCExp=This step refers to collagen triple helix (procollagen) formation. It is defective in osteogenesis imperfecta. It is not affected in Ehlers-Danlos syndrome.
|AnswerD=D
|AnswerD=D
|AnswerDExp=This step refers to the cleavage of the terminal regions of procollagen. It is not affected by vitamin C deficiency.
|AnswerDExp=This step refers to the cleavage of the terminal regions of procollagen. It is not affected in Ehlers-Danlos syndrome.
|AnswerE=E
|AnswerE=E
|AnswerEExp=This refers to collagen cross-linking via lysyl-oxidase (requires copper). This step is defective in Ehlers-Danlos disease. It is not affected by vitamin C deficiency.
|AnswerEExp=This refers to collagen cross-linking via lysyl-oxidase (requires copper). This step is the defective step in Ehlers-Danlos disease.
|RightAnswer=A
|EducationalObjectives=Ehlers-Danlos is a rare inherited disorder with certain forms characterized by defective corss-linking of collagen fibers.
|WBRKeyword=Scurvy, Vitamin C deficiency,
|References=Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest. 2001;107(9):1063-9.<br>
|Approved=No
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.
|RightAnswer=E
|WBRKeyword=Ehlers-Danlos Syndrome, Collagen sythesis, Lysyl oxidase, Collagen synthesis defects, COL5A1, Collagen,  
|Approved=Yes
}}
}}

Latest revision as of 01:18, 28 October 2020
Author [[PageAuthor::Serge Korjian M.D. (Reviewed by Serge Korjian)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Biochemistry
Sub Category SubCategory::Dermatology, SubCategory::General Principles
Prompt [[Prompt::A 6-year-old boy with poor medical follow-up presents for 3 days of high grade fever. Physical examination initially reveals pharyngeal exudates, but the physician notices that the child displays several bruises on his arms and legs. The mother explains that the bruises have been appearing and disappearing spontaneously since the child was approximately 6 months old. 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 disorder that is heterogeneous in presentation and pathologic mechanisms. Six subtypes of Ehlers-Danlos exist 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.

Educational Objective: Ehlers-Danlos is a rare inherited disorder with certain forms characterized by defective corss-linking of collagen fibers.
References: Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest. 2001;107(9):1063-9.
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.]]

Approved Approved::Yes
Keyword WBRKeyword::Ehlers-Danlos Syndrome, WBRKeyword::Collagen sythesis, WBRKeyword::Lysyl oxidase, WBRKeyword::Collagen synthesis defects, WBRKeyword::COL5A1, WBRKeyword::Collagen
Linked Question Linked::
Order in Linked Questions LinkedOrder::
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