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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson {{Alison}}
|QuestionAuthor=William J Gibson (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry, Genetics
Line 21: Line 21:
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry, Genetics
|SubCategory=General Principles
|SubCategory=General Principles
|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?
|Prompt=A 41-year-old woman presents to her primary care physician with complaints of distal weakness in her upper and lower extremities. Her past medical history is significant for cholecystecomy and chronic constipation. Upon further questioning, she reports some difficulty swallowing solids and liquids. On physical examination, the physician notes that the patient is unable to release her grip following contraction. When the thenar eminence was tapped using a tendon hammer, a prolonged muscle contraction is observed. Using a sample of this patient's DNA, which of the following techniques confirm the diagnosis?
|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.
|Explanation=Myotonic dystrophy subtype 1 (DM1 or MMD1 or Steinert's disease) is a autosomal dominant genetic disorder characterized by progressive distal muscle weakness of the upper and lower extremities. Patients often complain of foot drop or inability to perform physical activities that require intricate use of the hands (use tools or doorknobs). In addition, patients with myotonic dystrophy have frontal balding and unique facial features (temporal wasting and hatchet-appearance) caused by the wasting of the facial muscles and also resulting in ptosis and dysarthria. Patients may exhibit a "warm-up phenomenon", characterized by the improvement in strength of the handgrip myotonia upon repeated contractions (e.g. inability to release hand from doorknob following contraction). On physical examination, percussion myotonia may also be evaluated by percussion of the thenar eminence using a tendon hammer. Patients with myotonic dystophy are at-risk of several complications, including subcapsular cataracts, which eventually develop in almost all patients, cardiac conduction abnormalities (potentially fatal tachyarrhythmias), aspiration pneumonia and diaphragmatic weakness, endocrinopathies, intellectual deficits, cholecystitis and decreased esophageal peristalsis (increased tonicity of gallbladder sphincter and esophageal muscles, respectively), slow gastric emptying, constipation (may be due to pseudo-obstruction), or diarrhea and fecal incontinence.
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.
Myotonic dystophy has 2 subtypes:
* DM1 or MMD1 (Steinert's disease): Autosomal dominant disorder characterized by the presence of unstable CTG trinucleotide repeats (5' CTG 3') in the 3' untranslated region of the ''DMPK'' (myotonic dystrophy protein kinase) gene in chromosome 19q that normally encodes myosin kinase. The number of CTG repeats is directly associated with the clinical manifestations of the disease; normal individuals have less than 37 CTG repeats, asymptomatic patients with a pre-mutation have 37-50 CTG repeats, and patients with clinical myotonic distrophy have > 50 CTG repeats. The disease is characterized by anticipation, whereby children of patients with a pre-mutation (37-50 CTG repeats) may have longer repeats and develop manifestations of the disease.<br>
* DM2 or MMD2 (proximal myotonic myopathy): Autosomal dominant disorder caused by a mutation of ''ZNF9'' (zinc finger protein) gene in chromosome 3q that result in the expansion of CCTG (not CTG) repeats. Unlike DM1, the number of CCTG repeats does not correlate with the clinical manifestations of DM2. Symptoms begin at adulthood, including myotonia, proximal weakness, stiffness, and fatigue. Although it shares similar complications to DM1, DM2 is considered a milder disease. DM2 is not usually tested on USMLE.
 
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.


Mnemonic: SNoW DRoP.  Southern - DNA, Northern - RNA, Western - Protein.
Mnemonic: SNoW DRoP.  Southern - DNA, Northern - RNA, Western - Protein.
|AnswerA=Northern blot; 5’(CAG){{sub|n}}3’  probe
|AnswerA=Northern blot; 5'(CAG) {{sub|n}}3' 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.
|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=Northern 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=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=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'.
|AnswerE=Southern blot; 5’(CAA){{sub|n}}3’ probe
|AnswerE=Southern blot; 5'(CAA) {{sub|n}}3' probe
|AnswerEExp=While Sounthern blots are used to detect DNA, 5’ CAA 3’ is the repeat responsible for [[Friedrich’s ataxia]].
|AnswerEExp=While southern blots are used to detect DNA, 5' CAA 3' is the repeat responsible for [[Friedrich’s ataxia]].
|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.
|EducationalObjectives=Myotonic dystrophy subtype 1 is an autosomal dominant disorder characterized by the presence of unstable CTG trinucleotide repeats (5' CTG 3') in the 3' untranslated region of the''DMPK'' gene. Southern blotting detects the presence of certain sequences of DNA by using probes that have with a complementary sequence of labeled DNA.
|References=First Aid 2014 page 82.
|References=Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010;81:358-67.<br>
First Aid 2014 page 82
|RightAnswer=C
|RightAnswer=C
|WBRKeyword=Molecular biology, Laboratory, Blot, Trinucleotide repeat disorders, Myotonic dystrophy,  
|WBRKeyword=Molecular biology, Laboratory, Blot, Southern blot, Trinucleotide repeat disorders, Myotonic dystrophy, Probe, DNA sequence, Complementary DNA sequence, Steinert's disease, Handgrip myotonia, Percussion myotonia, Weakness, CTG repeats
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 00:09, 28 October 2020
Author [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Biochemistry, MainCategory::Genetics
Sub Category SubCategory::General Principles
Prompt [[Prompt::A 41-year-old woman presents to her primary care physician with complaints of distal weakness in her upper and lower extremities. Her past medical history is significant for cholecystecomy and chronic constipation. Upon further questioning, she reports some difficulty swallowing solids and liquids. On physical examination, the physician notes that the patient is unable to release her grip following contraction. When the thenar eminence was tapped using a tendon hammer, a prolonged muscle contraction is observed. Using a sample of this patient's DNA, which of the following techniques confirm the diagnosis?]]
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'.]]
Answer E [[AnswerE::Southern blot; 5'(CAA) n3' probe]]
Answer E Explanation [[AnswerEExp::While southern blots are used to detect DNA, 5' CAA 3' is the repeat responsible for Friedrich’s ataxia.]]
Right Answer RightAnswer::C
Explanation [[Explanation::Myotonic dystrophy subtype 1 (DM1 or MMD1 or Steinert's disease) is a autosomal dominant genetic disorder characterized by progressive distal muscle weakness of the upper and lower extremities. Patients often complain of foot drop or inability to perform physical activities that require intricate use of the hands (use tools or doorknobs). In addition, patients with myotonic dystrophy have frontal balding and unique facial features (temporal wasting and hatchet-appearance) caused by the wasting of the facial muscles and also resulting in ptosis and dysarthria. Patients may exhibit a "warm-up phenomenon", characterized by the improvement in strength of the handgrip myotonia upon repeated contractions (e.g. inability to release hand from doorknob following contraction). On physical examination, percussion myotonia may also be evaluated by percussion of the thenar eminence using a tendon hammer. Patients with myotonic dystophy are at-risk of several complications, including subcapsular cataracts, which eventually develop in almost all patients, cardiac conduction abnormalities (potentially fatal tachyarrhythmias), aspiration pneumonia and diaphragmatic weakness, endocrinopathies, intellectual deficits, cholecystitis and decreased esophageal peristalsis (increased tonicity of gallbladder sphincter and esophageal muscles, respectively), slow gastric emptying, constipation (may be due to pseudo-obstruction), or diarrhea and fecal incontinence.

Myotonic dystophy has 2 subtypes:

  • DM1 or MMD1 (Steinert's disease): Autosomal dominant disorder characterized by the presence of unstable CTG trinucleotide repeats (5' CTG 3') in the 3' untranslated region of the DMPK (myotonic dystrophy protein kinase) gene in chromosome 19q that normally encodes myosin kinase. The number of CTG repeats is directly associated with the clinical manifestations of the disease; normal individuals have less than 37 CTG repeats, asymptomatic patients with a pre-mutation have 37-50 CTG repeats, and patients with clinical myotonic distrophy have > 50 CTG repeats. The disease is characterized by anticipation, whereby children of patients with a pre-mutation (37-50 CTG repeats) may have longer repeats and develop manifestations of the disease.
  • DM2 or MMD2 (proximal myotonic myopathy): Autosomal dominant disorder caused by a mutation of ZNF9 (zinc finger protein) gene in chromosome 3q that result in the expansion of CCTG (not CTG) repeats. Unlike DM1, the number of CCTG repeats does not correlate with the clinical manifestations of DM2. Symptoms begin at adulthood, including myotonia, proximal weakness, stiffness, and fatigue. Although it shares similar complications to DM1, DM2 is considered a milder disease. DM2 is not usually tested on USMLE.

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.

Mnemonic: SNoW DRoP. Southern - DNA, Northern - RNA, Western - Protein.
Educational Objective: Myotonic dystrophy subtype 1 is an autosomal dominant disorder characterized by the presence of unstable CTG trinucleotide repeats (5' CTG 3') in the 3' untranslated region of theDMPK gene. Southern blotting detects the presence of certain sequences of DNA by using probes that have with a complementary sequence of labeled DNA.
References: Turner C, Hilton-Jones D. The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry. 2010;81:358-67.
First Aid 2014 page 82]]

Approved Approved::Yes
Keyword WBRKeyword::Molecular biology, WBRKeyword::Laboratory, WBRKeyword::Blot, WBRKeyword::Southern blot, WBRKeyword::Trinucleotide repeat disorders, WBRKeyword::Myotonic dystrophy, WBRKeyword::Probe, WBRKeyword::DNA sequence, WBRKeyword::Complementary DNA sequence, WBRKeyword::Steinert's disease, WBRKeyword::Handgrip myotonia, WBRKeyword::Percussion myotonia, WBRKeyword::Weakness, WBRKeyword::CTG repeats
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