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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson
|QuestionAuthor=William J Gibson (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics
|MainCategory=Genetics
Line 21: Line 21:
|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Neurology
|SubCategory=Neurology
|Prompt=A 12 year old male presents to the clinic for recurrent seizures. The child was born via normal vaginal delivery to consanguineous parents and no defects were observed at birth. The patient began experiencing seizures at the age of 4. The parents’ description of the seizures is consistent with a diagnosis of partial seizures.  The patient is mildly autistic, and suffers mental retardation. On physical exam, the patient has a long face with everted ears. On cardiac auscultation, a mid-systolic click followed by a systolic murmur is appreciated at the apex. Which of the following is true of the patient’s likely disease?
|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?
|Explanation=The patient in this vignette is suffering from Fragile X syndrome. Fragile X syndrome is caused by a trinucleotide expansion of CGG repeats in the FMR1 gene on the X chromosome. Expansion of CGG repeats beyond a certain threshold causes silencing of the FMR1 gene which leads to pathology.
|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.
Fragile X syndrome is the second most common cause of mental retardation, behind Down syndrome. Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone.  Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance. However, due to genetic anticipation and X-inactivation in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance.
 
[[File:202px-Fragile_x_syndrom.png|center|200px]]
 
Example of facial characteristics of patient with Fragile X.
|AnswerA=Caused by sporadic mutation
|AnswerA=Caused by sporadic mutation
|AnswerAExp=Fragile X syndrome is caused by a trinucleotide repeat on the X chromosome.  An example of a disease caused by spontaneous mutation is Rett syndrome.
|AnswerAExp=An example of a disease caused by spontaneous mutation is [[Rett syndrome]].
|AnswerB=Caused by trinucleotide repeat
|AnswerB=Caused by expansion of repeats
|AnswerBExp=See 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.
|AnswerC=Caused by chromosomal deletion
|AnswerC=Caused by chromosomal deletion
|AnswerCExp=Fragile X syndrome is caused by a trinucleotide repeat on the X chromosome.  An example of a disease caused by a chromosomal deletion is William’s syndrome, which is caused by a deletion of a part of chromosome 7.
|AnswerCExp=An example of a disease caused by a chromosomal deletion is [[Williams syndrome]], which is caused by a microdeletion on chromosome 7.
|AnswerD=Autosomal recessive inheritance
|AnswerD=Caused by autosomal recessive inheritance
|AnswerDExp=Fragile X syndrome is an X-linked disorder.  An example of an autosomal recessive disease is Tay-Sachs disease.
|AnswerDExp=An example of an autosomal recessive disease is [[Tay-Sachs disease]].
|AnswerE=Autosomal dominant inheritance
|AnswerE=Caused by autosomal dominant inheritance
|AnswerEExp=Fragile X syndrome is an X-linked disorder.  An example of an autosomal dominant disease is Marfan syndrome.
|AnswerEExp=An example of an autosomal dominant disease is [[Marfan syndrome]].
|EducationalObjectives=Fragile X syndrome is caused by expansion of CGG repeats in the FMR1 gene on the X Chromosome.
|EducationalObjectives=[[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=First Aid 2014 page 89
|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.<br>
First Aid 2014 page 89
|RightAnswer=B
|RightAnswer=B
|WBRKeyword=Genetics, Mental disability, Mental retardation, Trinucleotide repeat disorders, Fragile X disorder
|WBRKeyword=Mental retardation, Retardation, Repeat disorder, Nucleotide, Nucleotide repeat, Fragile X syndrome, Fragile X, Intellectual disability, CGG,
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:47, 27 October 2020
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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