A 37-year-old woman comes to the office due to increased tearfulness. She describes herself as "a happy person" at baseline but has felt low for the past 6 months. The patient frequently goes a week without leaving home and has to force herself to eat and clean. She has no suicidal thoughts or hallucinations. The patient's father died by suicide at age 41, and her paternal grandfather is said to have died of a "mental disease" at age 49. Temperature is 36.9 C (98.4 F), blood pressure is 121/77 mm Hg, pulse is 68/min, and respirations are 14/min. The patient seems restless during the examination, shifting frequently in her chair. She repeatedly raises her right arm in an abrupt, twisting motion that ends with smoothing her hair. Extraocular movement testing shows delayed initiation of voluntary saccades. Deep tendon reflexes are 3+ in both upper and lower extremities. She scores 25/30 on the Montreal Cognitive Assessment (normal: ≥26), losing points on measures of executive function and memory. The patient's disease is associated primarily with degeneration of neurons producing which of the following neurotransmitters?
Huntington disease | |
Clinical features |
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Findings |
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Management & prognosis |
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This patient's psychiatric symptoms (eg, feeling low, amotivation), cognitive impairment (eg, executive dysfunction, memory loss), family history (eg, paternal transmission of "mental disease"), and neurologic findings (eg, chorea, hyperreflexia) are consistent with Huntington disease (HD). HD is caused by an autosomal dominant CAG trinucleotide repeat expansion in the huntingtin (HTT) gene on chromosome 4p, with generational transmission often leading to growing CAG repeats and a progressively younger age of symptom onset (ie, anticipation).
The increasing CAG repeats cause increasing polyglutamine additions within the huntingtin protein, leading to abnormal protein conformation and aggregation as well as intracellular pathway disruption. These changes are responsible for cell death and atrophy that particularly affect the caudate nucleus and putamen (ie, neostriatum), which are rich in GABA-producing neurons. Degeneration of these neurons results in the characteristic features (particularly movement) associated with HD.
Early in the disease course, chorea may be mild and mistaken for restlessness, and patients may try to hide movements as purposeful (eg, smoothing one's hair). Other common neurologic findings in HD include hyperreflexia, delayed initiation of voluntary saccades (ie, normally quick coordinated eye movements between fixed points), and eventually dementia.
(Choice A) Loss of dopamine-producing neurons in the substantia nigra is associated with Parkinson disease, which causes a resting tremor, bradykinesia, and rigidity.
(Choice C) Glutamate is the major excitatory neurotransmitter in the CNS. Excess glutamate is implicated in neurodegenerative conditions (ie, glutamate excitotoxicity), but degeneration of glutamate-producing neurons is not associated with HD.
(Choices D and E) Norepinephrine (produced in the locus coeruleus) and serotonin (produced in the raphe nuclei) are implicated in major depressive disorder. Although this patient should be thoroughly assessed for depression because of its comorbidity with HD, degeneration of GABA-producing neurons is associated primarily with her predominant disease process.
Educational objective:
Huntington disease is an autosomal dominant disease of CAG trinucleotide repeat expansion characterized by psychiatric symptoms, cognitive impairment, and chorea. It is associated with preferential degeneration of GABA-producing neurons in the caudate nucleus and putamen.