A 46-year-old man presents with his wife to his primary care provider for depression and strange movements. His wife reports that her husband has not been himself for the last 2 months. Whereas he was previously outgoing and “the life of the party,” the patient is now irritable and withdrawn. He is a partner at an accounting firm, but his colleagues are threatening to fire him if he continues to perform poorly at work. The patient cannot explain the recent changes to his mood and tearfully admits he fears there is something seriously wrong with him. His wife says that he is getting worse. The patient’s medical history is significant for hypertension, for which he takes lisinopril. His family history is unknown as he was adopted. The patient met his mother once and never knew his father but was told he died in his 50s. He drinks a few glasses of wine per week and has never smoked. His temperature is 98.6°F (37°C), blood pressure is 141/87 mmHg, pulse is 81/min, and respirations are 12/min. On physical exam, the patient has a flat affect with a facial grimace and sudden jerky movements of his upper extremities. Which of the following is most likely to be seen on further workup?
Dorsal striatum atrophy on head CT
Neurofibrillary tangles on brain biopsy
Alpha-synuclein aggregates on brain biopsy
Frontotemporal atrophy on head CT
Dorsal striatum atrophy on head CT
This patient presents with recent mood changes, jerky movements of the upper extremities, and a history of early death in his father, which suggests a diagnosis of Huntington disease. Huntington disease is characterized by atrophy of the caudate nucleus, which is a structure of the dorsal striatum.

Huntington disease (HD) is an autosomal dominant trinucleotide (CAG) repeat disorder located on chromosome 4. HD typically presents with mood changes and abnormal movements (particularly chorea or myoclonus) over weeks to months. Although executive function can be affected early on, memory is usually preserved until relatively late in the disease. Frontotemporal dementia, in contrast, usually presents with behavioral changes, and Alzheimer disease has memory impairment as an early sign. Caudate atrophy is typically seen on head imaging in Huntington disease. This disease cannot be cured but supportive treatment includes benzodiazepines and tetrabenazine for symptomatic relief of muscle spasms.

Walker presents a review of the evidence regarding the etiology of Huntington disease. He discusses that typically the onset of symptoms is in middle age after affected individuals have had children. He recommends a better understanding of the function of the mutant protein in this disease.

Incorrect Answers:
Answer A: Alpha-synuclein aggregates would be found on brain biopsy in Parkinson disease and Lewy body dementia. Lewy body dementia is characterized by parkinsonism and visual hallucinations. Patients would present with cogwheel rigidity, bradykinesia, and a resting tremor. Treatment is with dopamine agonists such as carbidopa/levodopa.

Answer C: Frontotemporal atrophy is consistent with a diagnosis of frontotemporal dementia. Frontotemporal dementia presents primarily with early behavioral changes, and it would not present with myoclonus. Treatment is supportive as there is no cure for this disease. Patients and their spouses may require psychiatric support for changes in behavior.

Answer D: Neurofibrillary tangles on brain biopsy would suggest a diagnosis of Alzheimer disease. This disease presents with a slowly progressive cognitive decline in elderly patients. Patients have early loss of memory but have maintained motor function and behavior until later in the course of the disease.

Answer E: A positive 14-3-3 CSF assay would confirm the diagnosis of Creutzfeldt-Jakob disease (CJD). Although CJD may also present with mood changes and myoclonus, CJD most prominently causes rapidly progressive dementia early in life. Treatment is supportive and death occurs quickly.

Bullet Summary:
Huntington disease is an autosomal dominant trinucleotide repeat disorder located on chromosome 4 that causes caudate atrophy and presents with mood changes, abnormal movements, and subcortical dementia.