WBR0099

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Musculoskeletal/Rheumatology
Prompt	[[Prompt::A 10-year-old boy is brought to the pediatrician's office by his mother for chronic weakness. She reports that her child started to have trouble rising from chairs at the age of six. He has become progressively weaker over the past four years and now requires braces to walk. Physical examination is remarkable for proximal weakness of the upper and lower extremities. The pediatrician also notes atrophy of the gluteus maximus and accessory muscles of the pelvis, and unusually large calf muscles. The physician suspects a genetic disease and refers the patient to genetic testing. Which of the following mutations is most likely present in this patient? Normal Sequence: GGC TAC GTG AAG AAG TCT]]
Answer A	AnswerA::GGC TAC GTA AAG AAG TCT
Answer A Explanation	[[AnswerAExp::This sequence reflects a missense mutation, which is not usually a cause of Duchenne Muscular Dystrophy.]]
Answer B	AnswerB::GGT ACG TGA AGA AGA TCT
Answer B Explanation	[[AnswerBExp::The above sequence actually comprises two mutations. One mutation from GGC T -> GGT reflects a one base pair deletion. The other is a one base pair insertion after AAG AAG T... -> AAG AAG AT... . Thus, the first mutation disrupts the frame of the sequence and the second mutation restores it. The above sequence thus reflects 5 missense mutations with no nonsense mutations. The series of two mutations is extremely unlikely and the nature of the mutations is unlikely to be severe enough to cause Duchenne Muscular Dystrophy.]]
Answer C	AnswerC::GGC TAA GTG AAG AAG TCT
Answer C Explanation	[[AnswerCExp::This mutation reflects the insertion of an inappropriate stop codon (TAC-> TAA) and is therefore a nonsense mutation.]]
Answer D	AnswerD::GGC TAC GTG ATG AAG TCT
Answer D Explanation	AnswerDExp::This sequence reflects a missense mutation, which is not usually a cause of Duchenne Muscular Dystrophy.
Answer E	AnswerE::GGC TAC GTG AAG AAG AAG ...(x20)... TCT
Answer E Explanation	[[AnswerEExp::This mutation would be a repeat expansion, which is the cause of Huntington’s disease and not Duchenne Muscular Dystrophy.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient in this vignette is suffering from Duchenne Muscular Dystrophy. Duchenne muscular dystrophy (DMD) is a recessive X-linked form ofmuscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death. The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue. Typically, it becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates between the time the boy is 9 to 12 years of age. Most men affected with DMD become essentially “paralyzed from the neck down” by the age of 21.[10] Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Children often display a positive Gower’s sign (link). The DMD gene consists of 79 exons, making it one of the largest genes in the genome. While many thousands of mutations in the DMD gene have been observed, the majority of patients (~70%) harbor deletions of the gene. We know that the patient does not exhibit any structural changes in the gene, so the patient more likely has a mutation causing dysfunctional Dystophin protein. The most likely mutation to cause DMD in this patient is the nonsense mutation in C. Nonsense mutations are caused by the insertion of a premature stop codon. The following codons are stop codons DNA: TAA TGA TAG RNA: UAA (U Are Away) UGA (U Go Away) UAG (U Are Gone) Educational Objective: UAA is a stop codon. Premature stop codons are referred to as nonsense mutations and often lead to the production of a dysfunctional gene product. References: First Aid 2014 page 89; First Aid 2012 page 91]]
Approved	Approved::Yes
Keyword	WBRKeyword::Muscle, WBRKeyword::Muscular Dystrophy, WBRKeyword::Mutation, WBRKeyword::Gene, WBRKeyword::Nucleotide, WBRKeyword::Genetics, WBRKeyword::Weakness
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Order in Linked Questions	LinkedOrder::