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 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. 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 |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |