WBR0217

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Neurology
Prompt	[[Prompt::A 6-year-old boy is brought to the clinic for partial seizures. The patient was born via normal vaginal delivery to consanguineous parents. The parents state that the patient had delayed speech and motor skills compared to his peers when he was young. They also report that he has autistic-like behavior and suffers from mental retardation. On physical exam, the patient has a long face with everted ears. Cardiac auscultation is remarkable for a mid-systolic click followed by a systolic murmur that is best appreciated at the the 5th left mid-clavicular intercostal space. The physician suspects a genetic disease and orders genetic testing to confirm his suspicion. Which genetic disorder best characterizes this patient's condition?]]
Answer A	AnswerA::Caused by sporadic mutation
Answer A Explanation	[[AnswerAExp::An example of a disease caused by spontaneous mutation is Rett syndrome.]]
Answer B	AnswerB::Caused by expansion of repeats
Answer B Explanation	[[AnswerBExp::Fragile X syndrome is caused by a trinucleotide expansion of CGG repeats that affect the methylation and expression of the FMR1 gene on the X chromosome.]]
Answer C	AnswerC::Caused by chromosomal deletion
Answer C Explanation	[[AnswerCExp::An example of a disease caused by a chromosomal deletion is Williams syndrome, which is caused by a microdeletion on chromosome 7.]]
Answer D	AnswerD::Caused by autosomal recessive inheritance
Answer D Explanation	[[AnswerDExp::An example of an autosomal recessive disease is Tay-Sachs disease.]]
Answer E	AnswerE::Caused by autosomal dominant inheritance
Answer E Explanation	[[AnswerEExp::An example of an autosomal dominant disease is Marfan syndrome.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Fragile X syndrome is an X-linked genetic disorder that affects boys. It is caused by a trinucleotide expansion of CGG repeats that affect the methylation and expression of the FMR1 gene on the X chromosome. Expansion of CGG repeats beyond a certain threshold causes silencing of the FMR1 gene thereby leading to the manifestation of the disease. It is the second most common cause of intellectual disability following Down syndrome. Fragile X syndrome is characterized by hypotonia and delayed language development and motor milestones during early childhood. Also, patients have characteristic hand-flapping movements with poor eye contact. Behavioral characteristics suggestive of fragile X syndrome include ADHD-like features, impulsivity, repetitive movements, and easy irritability, which makes the autism spectrum disorder a differential diagnosis of fragile X syndrome. Additionally, boys with the syndrome may have post-pubertal macroorchidism (enlarged testes), prognathism, and a characteristic but variable face with large everted ears, long face, high-arched palate, gynecomastia, and teeth malocclusion. Additional abnormalities may include lordosis, heart defects such as mitral valve prolapse which is usually characterized by a mid-systolic click followed by a systolic murmur that is best appreciated at the mitral region (5th left mid-clavicular intercostal space), pectus excavatum, flat feet, shortening of the tubular bones of the hands, and joint laxity. Educational Objective: Fragile X syndrome is caused by a trinucleotide expansion of CGG repeats that affect the methylation and expression of the FMR1 gene on the X chromosome. References: Bagni C, Tassone F, Neri G, et al. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122(12):4314-22. First Aid 2014 page 89]]
Approved	Approved::Yes
Keyword	WBRKeyword::Mental retardation, WBRKeyword::Retardation, WBRKeyword::Repeat disorder, WBRKeyword::Nucleotide, WBRKeyword::Nucleotide repeat, WBRKeyword::Fragile X syndrome, WBRKeyword::Fragile X, WBRKeyword::Intellectual disability, WBRKeyword::CGG
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