WBR0098

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D., and Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Neurology
Prompt	[[Prompt::A 42-year-old woman presents to her physician for gradual onset of uncontrolled spastic movements. She reports she also started experiencing mood disturbances and difficulty performing her job for the past 3 months. Her past medical history is remarkable for gastro-esophageal reflux disease (GERD), for which she takes daily omeprazole. The patient denies smoking, alcohol intake, or illicit drug use. 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 children. She inquires about genetic testing. Which of the following is most likely present in this patient's genetic results?]]
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 and signs 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 threshold causes silencing of the FMR1 gene thereby leading to pathology. Fragile X syndrome is the second most common cause of mental retardation after 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 muscular hypotonia.]]
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 of the majority of patients by the age of 65. Early signs of the disease include loss of grip strength, and weakness in the neck and extremities.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::Huntington's disease (HD) is a uniformly fatal neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and mood disorders. Symptoms manifest among affected individuals between the ages of 20 and 50. Clinical findings include depression, progressive dementia, choreiform movements due to 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 is accompanied by selective neuronal loss and astrogliosis. Educational Objective: Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene located on chromosome 4. 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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