WBR0089

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 started 2 years ago and have been progressively worsening. The patient's father and grandfather died of similar symptoms. Levels of which of the following compounds is most likely imbalanced in this patient?]]
Answer A	AnswerA::Thyroxine
Answer A Explanation	AnswerAExp::Thyroxine imbalance is characteristic of hypo- or hyperthyroidism. To date, there is no evidence to show the association between thyroxine levels and HD.
Answer B	AnswerB::Epinephrine
Answer B Explanation	AnswerBExp::To date, there is no evidence to show the association between epinephrine levels and HD.
Answer C	AnswerC::Dopamine
Answer C Explanation	[[AnswerCExp::Dopamine is increased in schizophrenia, but decreased in Parkinson’s disease and depression. Recently, the role of dopamine imbalance was implicated in Huntington's disease. Imbalances of dopamine levels are directly correlated with motor dysfunction observed among patients with HD.]]
Answer D	AnswerD::ADH
Answer D Explanation	[[AnswerDExp::Excess ADH is seen among patients with SIADH. In contrast, low ADH levels or resistance to ADH receptors is seen in central and nephrogenic diabetes insipidus, respectively. To date, there is no evidence to show the association between ADH levels and HD.]]
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::C
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-related, kinetic movements, ranging from early dyskinesis to late hypokinesis. Although the true role of dopamine is still poorly understood, neurobiologic imbalances in dopamine activity, its receptors, and transporters are well-documented. Educational Objective: Huntington's disease is associated with a deficiency of GABA and acetylcholine in the brains of affected patients. The role of dopamine imbalances has recently emerged to show a relation between dopamine levels and motor symptoms related to Huntington's disease. 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::No
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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