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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson
|QuestionAuthor=William J Gibson {{Alison}}
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry, Genetics
Line 20: Line 20:
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry, Genetics
|SubCategory=General Principles
|SubCategory=General Principles
|Prompt=A 25 year old girl presents to her primary care physician complaining of generalized weakness.  She reports that the weakness is particularly pronounced in her hands, feet and neck. Furthermore, she reports some difficulty swallowing the multivitamins she takes daily.  On further questioning, she admits to greater than normal daytime sleepiness.  Past medical history significant is only for occasional gastrointestinal distress over the past 5 years. The young woman reports 3 sexual partners in the last six months.  The physician notes that the patient was unable to release her grip after shaking hands.  Which of the following techniques would allow a pathologist to confirm the diagnosis from a sample of the patient’s DNA?
|Prompt=A 25-year-old female presents to her primary care physician with complaints of generalized weakness, which is particularly pronounced in her hands, feet, and neck. On further questioning, she reports some difficulty swallowing the multivitamins she takes daily, and greater than normal daytime sleepiness.  Medical history is significant only for occasional gastrointestinal distress over the past 5 years. You note that the patient is unable to release her grip after shaking hands.  Which of the following techniques would allow a pathologist to confirm the diagnosis from a sample of the patient’s DNA?
|Explanation=The patient in this vignette is suffering from myotonic dystrophy.  Myotonic dystrophy is an autosomal dominant disorder characterized by progressive muscle weakness and hypotonia eventually leading to cardiopulmonary involvement and death in the majority of patients by the age of 65 [http://brain.oxfordjournals.org/content/121/8/1557.full.pdf]. Early signs of the disease include loss of grip strength, and weakness in the neck, feet and hands.  Speech and swallowing may become difficult for patient’s due to loss of muscle tone in the tongue and the esophagus. A useful clinical clue for diagnosis is the failure of spontaneous letting go of the hands following strong handshakes due to myotonia (delayed relaxation of muscles after contraction) which accompanies muscle weakness.
|Explanation=The patient in this scenario is most likely suffering from [[myotonic dystrophy]].  [[Myotonic dystrophy]] is an autosomal dominant disorder characterized by progressive muscle weakness and hypotonia, eventually leading to cardiopulmonary involvement and subsequent death in the majority of patients by the age of 65. Early signs of the disease include loss of grip strength and weakness in the neck, feet, and hands.  Speech and swallowing may become difficult for patients due to loss of muscle tone in the tongue and the esophagus. Frequently, patients with the disease are unable to relax their hands following handshakes, due to [[myotonia]] (delayed relaxation of muscles after contraction) which accompanies muscle weakness.
Myotonic dystrophy is caused by expansion of a CTG triplet repeat in the DMPK gene*. Like other triplet repeat diseases such as Huntington’s, myotonic dystrophy can cause earlier and more severe symptoms in successive generations due to anticipation.  There is currently no cure for or treatment specific to myotonic dystrophy.
Myotonic dystrophy is caused by expansion of a CTG triplet repeat in the [[DMPK]] gene. A second form of [[myotonic dystrophy]] is caused by the expansion of a CCTG repeat in the ZNF9 gene. Like other triplet repeat diseases, such as [[Huntington’s disease]], [[myotonic dystrophy]] can result in more severe symptoms with an earlier onset in successive generations (anticipation).  There is currently no cure or treatment specific to [[myotonic dystrophy]].


Southern blots are used to detect the presence of a sequence of DNA.  One common way to assess the repeat length of an individual’s DNA is to subject the genomic DNA of the individual to polymerase chain reaction in order to amplify the segment containing the repeat.  The amplified DNA is then subjected to electrophoresis and probed with a complementary sequence of labeled DNA. The labeled band would appear higher when the repeat length of the DMPK gene is increased.  Thus, PCR with Southern blotting is a method of measuring repeat length for myotonic dystrophy.
Southern blots are used to detect the presence of a sequence of DNA.  To assess the repeat length of an individual’s DNA, genomic DNA of the individual is subjected to [[polymerase chain reaction]] (PCR), in order to amplify the segment containing the repeat.  The amplified DNA is then subjected to [[electrophoresis]] and probed with a complementary sequence of labeled DNA. Southern blotting is a method used to detect a specific fragment of a DNA sequesnce.


'''Wiki-mnemonic:''' SNoW DRoP.  Southern - DNA, Northern - RNA, Western - Protein.
* Wiki-mnemonic: SNoW DRoP.  Southern - DNA, Northern - RNA, Western - Protein.


'''Educational Objective:''' The CTG repeat in the DMPK gene is associated with myotonic dystrophy.  Southern blotting is used to detect the presence of certain sequences of DNA.  
|EducationalObjectives= The CTG repeat in the DMPK gene is associated with myotonic dystrophy.  Southern blotting is used to detect the presence of certain sequences of DNA.  


'''References:''' First Aid 2012 page 92.
|References= First Aid 2012 page 82.


* A second form of myotonic dystrophy is caused by expansion of a CCTG repeat in the ZNF9 gene.  This is not tested on the USMLE.
*  
|AnswerA=Northern blot; 5’(CAG){{sub|n}}3’  probe
|AnswerA=Northern blot; 5’(CAG){{sub|n}}3’  probe
|AnswerAExp='''Incorrect:''' Norther blots are used to detect RNA, not DNA.  The patient’s RNA is subjected to electrophoresis and probed with a labeled DNA probe.
|AnswerAExp= Northern blots are used to detect RNA, not DNA.  The patient’s RNA is subjected to electrophoresis and probed with a labeled DNA probe.
|AnswerB=Northern blot; 3’(CTG){{sub|n}}5’  probe
|AnswerB=Northern blot; 3’(CTG){{sub|n}}5’  probe
|AnswerBExp='''Incorrect:''' Norther blots are used to detect RNA, not DNA.  The patient’s RNA is subjected to electrophoresis and probed with a labeled DNA probe.
|AnswerBExp= Northern blots are used to detect RNA, not DNA.  The patient’s RNA is subjected to electrophoresis and probed with a labeled DNA probe.
|AnswerC=Southern blot; 5’(CAG){{sub|n}}3’  probe
|AnswerC=Southern blot; 5’(CAG){{sub|n}}3’  probe
|AnswerCExp='''Correct:''' Southern blots are used to detect the presence of certain sequences of DNA.  The probe 5’(CAG) 3’ is the reverse complement of the 5‘CTG 3’ repeat responsible for myotonic dystrophy.  Coincidentally, 5’ CAG 3’ is the repeat responsible for Huntington’s disease.
|AnswerCExp= Southern blots are used to detect the presence of certain sequences of DNA.  The probe 5’(CAG) 3’ is the reverse complement of the 5‘CTG 3’ repeat responsible for [[myotonic dystrophy]].  Coincidentally, 5’ CAG 3’ is the repeat responsible for Huntington’s disease.
|AnswerD=Southern blot; 5’(TCG){{sub|n}}3’  probe
|AnswerD=Southern blot; 5’(TCG){{sub|n}}3’  probe
|AnswerDExp='''Incorrect:''' The repeat associated with myotonic dystrophy is 5‘ CTG 3’.  The reverse complement of 5’ CTG 3’ is 5’ CAG  3’ either of these sequences could be used to detect the repeated region of DNA.
|AnswerDExp= The repeat associated with [[myotonic dystrophy]] is 5‘ CTG 3’.  The reverse complement of 5’ CTG 3’ is 5’ CAG  3’ either of these sequences could be used to detect the repeated region of DNA.
|AnswerE=Southern blot; 5’(CAA){{sub|n}}3’ probe
|AnswerE=Southern blot; 5’(CAA){{sub|n}}3’ probe
|AnswerEExp='''Incorrect:''' While Sounthern blots are used to detect DNA, 5’ CAA 3’ is the repeat responsible for Friedrich’s ataxia.
|AnswerEExp= While Sounthern blots are used to detect DNA, 5’ CAA 3’ is the repeat responsible for [[Friedrich’s ataxia]].
|RightAnswer=C
|RightAnswer=C
|Approved=Yes
|Approved=Yes
}}
}}

Revision as of 17:37, 11 July 2014
Author [[PageAuthor::William J Gibson (Reviewed by Alison Leibowitz)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Biochemistry, MainCategory::Genetics
Sub Category SubCategory::General Principles
Prompt [[Prompt::A 25-year-old female presents to her primary care physician with complaints of generalized weakness, which is particularly pronounced in her hands, feet, and neck. On further questioning, she reports some difficulty swallowing the multivitamins she takes daily, and greater than normal daytime sleepiness. Medical history is significant only for occasional gastrointestinal distress over the past 5 years. You note that the patient is unable to release her grip after shaking hands. Which of the following techniques would allow a pathologist to confirm the diagnosis from a sample of the patient’s DNA?]]
Answer A [[AnswerA::Northern blot; 5’(CAG)n3’ probe]]
Answer A Explanation AnswerAExp::Northern blots are used to detect RNA, not DNA. The patient’s RNA is subjected to electrophoresis and probed with a labeled DNA probe.
Answer B [[AnswerB::Northern blot; 3’(CTG)n5’ probe]]
Answer B Explanation AnswerBExp::Northern blots are used to detect RNA, not DNA. The patient’s RNA is subjected to electrophoresis and probed with a labeled DNA probe.
Answer C [[AnswerC::Southern blot; 5’(CAG)n3’ probe]]
Answer C Explanation [[AnswerCExp::Southern blots are used to detect the presence of certain sequences of DNA. The probe 5’(CAG) 3’ is the reverse complement of the 5‘CTG 3’ repeat responsible for myotonic dystrophy. Coincidentally, 5’ CAG 3’ is the repeat responsible for Huntington’s disease.]]
Answer D [[AnswerD::Southern blot; 5’(TCG)n3’ probe]]
Answer D Explanation [[AnswerDExp::The repeat associated with myotonic dystrophy is 5‘ CTG 3’. The reverse complement of 5’ CTG 3’ is 5’ CAG 3’ either of these sequences could be used to detect the repeated region of DNA.]]
Answer E [[AnswerE::Southern blot; 5’(CAA)n3’ probe]]
Answer E Explanation [[AnswerEExp::While Sounthern blots are used to detect DNA, 5’ CAA 3’ is the repeat responsible for Friedrich’s ataxia.]]
Right Answer RightAnswer::C
Explanation [[Explanation::The patient in this scenario is most likely suffering from myotonic dystrophy. Myotonic dystrophy is an autosomal dominant disorder characterized by progressive muscle weakness and hypotonia, eventually leading to cardiopulmonary involvement and subsequent death in the majority of patients by the age of 65. Early signs of the disease include loss of grip strength and weakness in the neck, feet, and hands. Speech and swallowing may become difficult for patients due to loss of muscle tone in the tongue and the esophagus. Frequently, patients with the disease are unable to relax their hands following handshakes, due to myotonia (delayed relaxation of muscles after contraction) which accompanies muscle weakness.

Myotonic dystrophy is caused by expansion of a CTG triplet repeat in the DMPK gene. A second form of myotonic dystrophy is caused by the expansion of a CCTG repeat in the ZNF9 gene. Like other triplet repeat diseases, such as Huntington’s disease, myotonic dystrophy can result in more severe symptoms with an earlier onset in successive generations (anticipation). There is currently no cure or treatment specific to myotonic dystrophy.

Southern blots are used to detect the presence of a sequence of DNA. To assess the repeat length of an individual’s DNA, genomic DNA of the individual is subjected to polymerase chain reaction (PCR), in order to amplify the segment containing the repeat. The amplified DNA is then subjected to electrophoresis and probed with a complementary sequence of labeled DNA. Southern blotting is a method used to detect a specific fragment of a DNA sequesnce.

  • Wiki-mnemonic: SNoW DRoP. Southern - DNA, Northern - RNA, Western - Protein.

Educational Objective: The CTG repeat in the DMPK gene is associated with myotonic dystrophy. Southern blotting is used to detect the presence of certain sequences of DNA.
References: First Aid 2012 page 82.

  • ]]
Approved Approved::Yes
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