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|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=Dermatology, General Principles
|SubCategory=Dermatology, General Principles
|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?
|Prompt=A 4 year old girl presents to the emergency room for 2 episodes of blood in the stools. History initially is inconclusive, but upon further questioning the mother explains that her child was recently diagnosed with a rare disorder that causes her to have very stretchy skin, and joints that can extend beyond the normal range. Considering this patient has a mutation in type 1 collagen, what co-factor is essential in the defective enzyme in this patient?
|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. Lysyl-oxidase requires copper as a cofactor to function effectively. Ehlers-Danlos classically presents with skin hyperextensibility, cutaneous fragility, joint hypermobility, and vascular anomalies.Mutations often involve the COL-A genes.


[[Image:Collagen1.jpg|400px]]
|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 due to abnormal lysyl-oxidase. Lysyl oxidase requires copper as a cofactor.
Learning objective: Ehlers-Danlos is a rare inherited disorder with certain forms characterized by defective corss-linking of collagen fibers.


Reference:
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.
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.
Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest. 2001;107(9):1063-9.
|AnswerA=A
|AnswerA=Selenium
|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.
|AnswerAExp=Selenium is a known cofactor for thyroid hormone deiodinases. It has no function with lysyl-oxidase.
|AnswerB=B
|AnswerB=Niacin
|AnswerBExp=This step refers to glycosylation of specific residues in the collagen chain. It is not affected in Ehlers-Danlos syndrome.
|AnswerBExp=Niacin also known as vitamin B3 is an important cofactor for hydrogen transfer processes as NAD and NADP. It has no function with lysyl-oxidase.
|AnswerC=C
|AnswerC=Zinc
|AnswerCExp=This step refers to collagen triple helix (procollagen) formation. It is defective in osteogenesis imperfecta. It is not affected in Ehlers-Danlos syndrome.
|AnswerCExp=Zinc is very important in the formation of zinc fingers which constitute parts of some transcription factors. It has no function with lysyl-oxidase.
|AnswerD=D
|AnswerD=Copper
|AnswerDExp=This step refers to the cleavage of the terminal regions of procollagen. It is not affected in Ehlers-Danlos syndrome.
|AnswerDExp=Copper is important for the proper functioning of lysyl-oxidase an enzyme defective in certain forms of Ehlers-Danlos syndrome.
|AnswerE=E
|AnswerE=Biotin
|AnswerEExp=This refers to collagen cross-linking via lysyl-oxidase (requires copper). This step is the defective step in Ehlers-Danlos disease.
|AnswerEExp=Biotin functions as a cofactor for carboxylation reactions (Acetyl-CoA carboxylase, methylcrotonyl-CoA carboxylase, and propionyl-CoA carboxylase). It has no function with lysyl-oxidase.
|RightAnswer=E
|RightAnswer=D
|WBRKeyword=Ehlers-Danlos Syndrome, Collagen sythesis, Lysyl oxidase
|WBRKeyword=Ehlers-Danlos Syndrome, Collagen sythesis, Lysyl oxidase, Copper
|Approved=No
|Approved=No
}}
}}

Revision as of 23:45, 23 October 2013
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 4 year old girl presents to the emergency room for 2 episodes of blood in the stools. History initially is inconclusive, but upon further questioning the mother explains that her child was recently diagnosed with a rare disorder that causes her to have very stretchy skin, and joints that can extend beyond the normal range. Considering this patient has a mutation in type 1 collagen, what co-factor is essential in the defective enzyme in this patient?]]
Answer A AnswerA::Selenium
Answer A Explanation AnswerAExp::Selenium is a known cofactor for thyroid hormone deiodinases. It has no function with lysyl-oxidase.
Answer B AnswerB::Niacin
Answer B Explanation AnswerBExp::Niacin also known as vitamin B3 is an important cofactor for hydrogen transfer processes as NAD and NADP. It has no function with lysyl-oxidase.
Answer C AnswerC::Zinc
Answer C Explanation AnswerCExp::Zinc is very important in the formation of zinc fingers which constitute parts of some transcription factors. It has no function with lysyl-oxidase.
Answer D AnswerD::Copper
Answer D Explanation AnswerDExp::Copper is important for the proper functioning of lysyl-oxidase an enzyme defective in certain forms of Ehlers-Danlos syndrome.
Answer E AnswerE::Biotin
Answer E Explanation AnswerEExp::Biotin functions as a cofactor for carboxylation reactions (Acetyl-CoA carboxylase, methylcrotonyl-CoA carboxylase, and propionyl-CoA carboxylase). It has no function with lysyl-oxidase.
Right Answer RightAnswer::D
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. Lysyl-oxidase requires copper as a cofactor to function effectively. Ehlers-Danlos classically presents with skin hyperextensibility, cutaneous fragility, joint hypermobility, and vascular anomalies.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 due to abnormal lysyl-oxidase. Lysyl oxidase requires copper as a cofactor.

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, WBRKeyword::Copper
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