WBR0310

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry, MainCategory::Genetics
Sub Category	SubCategory::General Principles
Prompt	[[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?]]
Answer A	[[AnswerA::Northern blot; 5’(CAG)n3’ probe]]
Answer A Explanation	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.
Answer B	[[AnswerB::Northern blot; 3’(CTG)n5’ probe]]
Answer B Explanation	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.
Answer C	[[AnswerC::Southern blot; 5’(CAG)n3’ probe]]
Answer C Explanation	[[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.]]
Answer D	[[AnswerD::Southern blot; 5’(TCG)n3’ probe]]
Answer D Explanation	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.
Answer E	[[AnswerE::Southern blot; 5’(CAA)n3’ probe]]
Answer E Explanation	AnswerEExp::'''Incorrect:''' 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 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 [1]. 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. 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. 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. 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 92. 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. Educational Objective: References: ]]
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