WBR0098

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Neurology
Prompt	[[Prompt::A 36 year old woman presents to her physician for the gradual onset of uncontrolled spastic movements. She reports having begun experiencing mood disturbances and difficulty performing her job at work 3 months prior to the onset of her movement disorder began. Further questioning reveals that her father died of a neurodegenerative condition at the age of 50. The patient has researched her likely condition on the internet and is most concerned about having passed the trait onto her kids. She inquires about genetic testing. Which of the following would one expect to find in this patient?]]
Answer A	AnswerA::Loss of function mutation
Answer A Explanation	AnswerAExp::Huntington’s disease is caused by a trinucleotide expansion. Autosomal recessive diseases are usually caused by loss of function mutations.
Answer B	AnswerB::Expansion of CAA repeats
Answer B Explanation	[[AnswerBExp::Friedreich's ataxia is an autosomal recessive disorder that occurs when the FXN gene contains amplified intronic GAA repeats. Symptoms of Friedreich's ataxia include hearing loss, muscle weakness, gait disturbances, scoliosis and hypertrophic cardiomyopathy.]]
Answer C	AnswerC::Expansion of CAG repeats
Answer C Explanation	AnswerCExp::CAG trinucleotide repeats are responsible for Huntington's disease.
Answer D	AnswerD::Expansion of CGG repeats
Answer D Explanation	[[AnswerDExp::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 thereby leading to pathology. 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.]]
Answer E	AnswerE::Expansion of CTG repeats
Answer E Explanation	[[AnswerEExp::Myotonic dystrophy is an autosomal dominant disorder caused by expansion of CTG repeats in the DMPK gene. It is characterized by progressive muscle weakness and hypotonia eventually leading to cardiopulmonary involvement and death in the majority of patients by the age of 65 [1]. 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 patient’s due to loss of muscle tone in the tongue and the esophagus.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient in this vignette has Huntington’s disease, a uniformly fatal neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline. Symptoms manifest in affected individuals between the ages of 20 and 50. Clinical findings include depression, progressive dementia, choreiform movements, caudate atrophy and decreased levels of both GABA and acetylcholine in the brain. It is a trinucleotide repeat disorder caused by (CAG)n repeats in the Huntingtin gene located on chromosome 4. Expansion of this CAG triplet repeat stretch within the Huntingtin gene results in a different (mutant) form of the protein that gradually damages cells in the brain through mechanisms that are not fully understood. The disease is inherited in an autosomal dominant manner and displays genetic anticipation. This anticipation is thought to be caused by polymerase "slippage" during DNA replication in germ cells, thereby increasing the length of the repeat segment. The common neuropathology in Huntington's disease occurs within the neostriatum, in which gross atrophy of the caudate and putamen nuclei occurs and accompanied by selective neuronal loss and astrogliosis. Wiki-mnemomic: You hunt animals and put them in the CAGe: Huntington Disease is a CAG repeat disorder. Educational Objective: Huntington's disease is caused by a CAG repeat expansion. References: First Aid 2014 page 454]]
Approved	Approved::Yes
Keyword	WBRKeyword::Huntington's disease, WBRKeyword::Huntington disease, WBRKeyword::Genetics, WBRKeyword::Inherited, WBRKeyword::Anticipation, WBRKeyword::trinucleotide repeat disorders, WBRKeyword::Inheritance, WBRKeyword::Neurodegenerative
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