WBR0310

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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