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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor={{Ochuko}} (Reviewed by Will Gibson, [[user: Jad Al Danaf|Jad Al Danaf]], {{Rim}})
|QuestionAuthor={{Ochuko}} (Reviewed by Will Gibson, Yazan Daaboul, [[user: Jad Al Danaf|Jad Al Danaf]], and {{Rim}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|MainCategory=Biochemistry, Genetics
|MainCategory=Biochemistry
|SubCategory=Neurology
|SubCategory=Neurology
|Prompt=A 46-year-old man is brought to the emergency department by his son for worsening jerky movements, progressive loss of memory and aggressiveness. His symptoms began 2 years ago and have progressively worsened. The patient's father and grandfather died of similar symptoms. Deficiency of which of the following is most likely responsible for this patient's symptoms?
|Prompt=A 46-year-old man is brought to the emergency department by his son for worsening jerky movements, progressive loss of memory, and aggressiveness. His symptoms have only recently begun. The patient's father and grandfather died of similar symptoms. Deficiency of which of the following is most likely responsible for this patient's early symptoms?
|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]], [[chorea|choreiform movements]], [[caudate nucleus|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.
|Explanation=[[Huntington’s disease]] (HD) is an autosomal dominant neurodegenerative genetic disease caused by polyglutamine expansion in the coding region of the gene ''IT15'' that codes for the huntingtin (''HTT'') protein. Huntington's disease is characterized by the presence of unstable trinucleotide repeats (CAG) in the ''Huntingtin'' (HTT) gene located on the short arm of chromosome 4 (4p63).  


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.
Most patients with the HD mutation lead a normal life during early adulthood. Symptoms manifest in affected individuals between the ages of 20 and 50. Clinically, Huntington's disease is characterized by the presence of the triad: psychiatric symptoms, motor dysfunction, and cognitive impairment due to [[caudate]] atrophy and deterioration of the putamen and frontal cortex. Patients with HD classically have decreased levels of both [[GABA]] and [[acetylcholine]] in the brain.


The common neuropathology in [[Huntington's disease]] occurs within the [[neostriatum]], in which gross atrophy of the [[caudate nucleus|caudate]] and [[putamen]] nuclei occurs and accompanied by selective neuronal loss and [[astrogliosis]].
Neuronol loss in HD is selective. While striatal projection neurons are affected, striatal interneurons seem to be spared. Accordingly, abnormal jerky movements observed in HD patients is attributed to the loss of unique medium-sized spiny neurons (MSNs) that secrete GABA, an inhibitory neurotransmitter, between the striatum and globus pallidus. In early HD, loss of inhibitory neurones leads to hyperactivity in the dopamine (DA) pathways, manifesting as chorea. Late in the course of the disease, DA release is reduced. These alterations are consistent with patients' biphasic, temporal kinetic movements, ranging from early dyskinesis to late hypokinesis.
 
Wiki-mnemomic: You hunt animals and put them in the '''CAG'''e: Huntington Disease is a '''CAG''' repeat disorder.
|AnswerA=Serotonin
|AnswerA=Serotonin
|AnswerAExp=[[Serotonin]] is decreased in [[anxiety]], [[depression]] and increased in [[Parkinson’s disease]]
|AnswerAExp=[[Serotonin]] is decreased in [[anxiety]], [[depression]] and increased in [[Parkinson’s disease]]
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|AnswerBExp=Patients with Huntington's disease have a deficiency of the neurotransmitters [[GABA]] and [[acetylcholine]].
|AnswerBExp=Patients with Huntington's disease have a deficiency of the neurotransmitters [[GABA]] and [[acetylcholine]].
|AnswerC=Dopamine
|AnswerC=Dopamine
|AnswerCExp=[[Dopamine]] is increased in [[schizophrenia]], but decreased in [[Parkinson’s disease]] and [[depression]].  It is not known to be altered in [[Huntington's disease]].
|AnswerCExp=[[Dopamine]] is increased in [[schizophrenia]], but decreased in [[Parkinson’s disease]] and [[depression]].
|AnswerD=Glutamate
|AnswerD=Glutamate
|AnswerDExp=[[Glutamate]] is used by the brain to synthesize [[GABA]] but its deficiency is not implicated in the pathogenesis of [[Huntington's disease]]. Instead, neurons are thought to undergo "excitotoxic death" in Huntington disease, whereby mutant huntingtin protein increases glutamatergic neurotransmission through [[NMDA receptors]] to neurotoxic levels.
|AnswerDExp=[[Glutamate]] is used by the brain to synthesize [[GABA]] but its deficiency is not implicated in symptoms among patients with [[Huntington's disease]]. Instead, animal studies showed that formation of neuronal polyglutamine aggregates due to abnormal uptake of glutamate neurons is thought to contribute to the phenotype and neuronal cell death in HD by excitotoxicity and overactivation of NMDA receptor, a glutamate recptor, that mediates MSN neurodegeneration.
|AnswerE=Norepinephrine
|AnswerE=Norepinephrine
|AnswerEExp=[[Norepinephrine]] is a neurotransmitter that is increased in [[anxiety]] and decreased in [[depression]].
|AnswerEExp=[[Norepinephrine]] is a neurotransmitter that is increased in [[anxiety]] and decreased in [[depression]]. It has no role in HD.
|EducationalObjectives=[[Huntington's disease]] is associated with a deficiency of [[GABA]] and [[acetylcholine]] in the brains of affected patients. [[Huntington's disease]] is the most common genetic cause of abnormal involuntary movements called chorea, which is why the disease used to be called Huntington's chorea.
|EducationalObjectives=[[Huntington's disease]] is associated with a deficiency of [[GABA]] and [[acetylcholine]] in the brains of affected patients.
|References=First Aid 2014 page 454
|References=Chen JY, Wang EA, Cepeda C, Levine MS. Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility. Front Neurosci. 2013. eCollection 2013.
 
van Oostrom JCH, Dekker M, Willemsen ATM, et al. Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington's disease. Eur J Neurol. 2009;16(2):226-31.
 
Lievens JC, Woodman B, Mahal A, et al. Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol Dis. 2001;8(5):807-21.
First Aid 2014 page 454
|RightAnswer=B
|RightAnswer=B
|WBRKeyword=Brain, Trinucleotide repeat, Neurodegenerative, Huntington disease, Huntington's disease, Genetics, Neurology, Depression,  
|WBRKeyword=Brain, Trinucleotide repeat, Neurodegenerative, Huntington disease, Huntington's disease, Genetics, Neurology, Depression,
|Approved=Yes
|Approved=Yes
}}
}}

Revision as of 15:47, 28 August 2014
Author [[PageAuthor::Ogheneochuko Ajari, MB.BS, MS [1] (Reviewed by Will Gibson, Yazan Daaboul, Jad Al Danaf, and Rim Halaby, M.D. [2])]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Biochemistry
Sub Category SubCategory::Neurology
Prompt [[Prompt::A 46-year-old man is brought to the emergency department by his son for worsening jerky movements, progressive loss of memory, and aggressiveness. His symptoms have only recently begun. The patient's father and grandfather died of similar symptoms. Deficiency of which of the following is most likely responsible for this patient's early symptoms?]]
Answer A AnswerA::Serotonin
Answer A Explanation [[AnswerAExp::Serotonin is decreased in anxiety, depression and increased in Parkinson’s disease]]
Answer B AnswerB::GABA
Answer B Explanation [[AnswerBExp::Patients with Huntington's disease have a deficiency of the neurotransmitters GABA and acetylcholine.]]
Answer C AnswerC::Dopamine
Answer C Explanation [[AnswerCExp::Dopamine is increased in schizophrenia, but decreased in Parkinson’s disease and depression.]]
Answer D AnswerD::Glutamate
Answer D Explanation [[AnswerDExp::Glutamate is used by the brain to synthesize GABA but its deficiency is not implicated in symptoms among patients with Huntington's disease. Instead, animal studies showed that formation of neuronal polyglutamine aggregates due to abnormal uptake of glutamate neurons is thought to contribute to the phenotype and neuronal cell death in HD by excitotoxicity and overactivation of NMDA receptor, a glutamate recptor, that mediates MSN neurodegeneration.]]
Answer E AnswerE::Norepinephrine
Answer E Explanation [[AnswerEExp::Norepinephrine is a neurotransmitter that is increased in anxiety and decreased in depression. It has no role in HD.]]
Right Answer RightAnswer::B
Explanation [[Explanation::Huntington’s disease (HD) is an autosomal dominant neurodegenerative genetic disease caused by polyglutamine expansion in the coding region of the gene IT15 that codes for the huntingtin (HTT) protein. Huntington's disease is characterized by the presence of unstable trinucleotide repeats (CAG) in the Huntingtin (HTT) gene located on the short arm of chromosome 4 (4p63).

Most patients with the HD mutation lead a normal life during early adulthood. Symptoms manifest in affected individuals between the ages of 20 and 50. Clinically, Huntington's disease is characterized by the presence of the triad: psychiatric symptoms, motor dysfunction, and cognitive impairment due to caudate atrophy and deterioration of the putamen and frontal cortex. Patients with HD classically have decreased levels of both GABA and acetylcholine in the brain.

Neuronol loss in HD is selective. While striatal projection neurons are affected, striatal interneurons seem to be spared. Accordingly, abnormal jerky movements observed in HD patients is attributed to the loss of unique medium-sized spiny neurons (MSNs) that secrete GABA, an inhibitory neurotransmitter, between the striatum and globus pallidus. In early HD, loss of inhibitory neurones leads to hyperactivity in the dopamine (DA) pathways, manifesting as chorea. Late in the course of the disease, DA release is reduced. These alterations are consistent with patients' biphasic, temporal kinetic movements, ranging from early dyskinesis to late hypokinesis.
Educational Objective: Huntington's disease is associated with a deficiency of GABA and acetylcholine in the brains of affected patients.
References: Chen JY, Wang EA, Cepeda C, Levine MS. Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility. Front Neurosci. 2013. eCollection 2013.

van Oostrom JCH, Dekker M, Willemsen ATM, et al. Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington's disease. Eur J Neurol. 2009;16(2):226-31.

Lievens JC, Woodman B, Mahal A, et al. Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol Dis. 2001;8(5):807-21. First Aid 2014 page 454]]

Approved Approved::Yes
Keyword WBRKeyword::Brain, WBRKeyword::Trinucleotide repeat, WBRKeyword::Neurodegenerative, WBRKeyword::Huntington disease, WBRKeyword::Huntington's disease, WBRKeyword::Genetics, WBRKeyword::Neurology, WBRKeyword::Depression
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