Neurology · Movement Disorders
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Huntington disease is an autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the HTT gene on chromosome 4.
The pathophysiology involves anticipation, where the disease presents at an earlier age and with increased severity in successive generations due to trinucleotide repeat expansion during spermatogenesis.
Clinical presentation is characterized by the triad of chorea (involuntary, jerky movements), psychiatric disturbances (depression, irritability), and progressive dementia.
Neuroimaging via MRI typically reveals atrophy of the caudate nucleus and putamen, leading to ex vacuo ventriculomegaly of the frontal horns of the lateral ventricles.
The underlying mechanism involves the loss of GABAergic neurons in the striatum, specifically the caudate nucleus, resulting in disinhibition of the thalamus.
Management of chorea is primarily symptomatic using VMAT2 inhibitors such as tetrabenazine or deutetrabenazine.
Psychiatric symptoms, particularly depression and irritability, are common early manifestations and often require treatment with SSRIs or antipsychotics.
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A 42-year-old man is brought to the clinic by his wife due to progressive personality changes and involuntary movements. She notes that he has become increasingly irritable and impulsive over the past year. On physical examination, the patient exhibits fidgety, jerky movements of his hands and feet that he attempts to incorporate into purposeful actions. His father died at age 50 from a similar condition. MRI of the brain demonstrates atrophy of the caudate nuclei with associated dilation of the frontal horns of the lateral ventricles.
What is the most likely diagnosis?
Huntington disease
The patient presents with the classic triad of chorea, psychiatric symptoms, and family history, supported by the pathognomonic finding of caudate atrophy on MRI, which confirms Huntington disease.
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Etiology / Epidemiology
Autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion on chromosome 4.
Clinical Manifestations
Triad of chorea, psychiatric disturbances, and dementia; onset typically 30-50 years old.
Diagnosis
Confirmed via genetic testing demonstrating >36-40 CAG repeats; MRI shows caudate atrophy.
Treatment
Tetrabenazine is first-line for chorea; suicidal ideation is a major management concern.
Prognosis
Progressive decline leading to death within 15-20 years of symptom onset; pneumonia is common.
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Epidemiology & Etiology
Inherited in an autosomal dominant pattern with anticipation, where symptoms appear earlier in successive generations. The mutation involves an expanded CAG repeat in the huntingtin gene. Prevalence is approximately 5-10 per 100,000 individuals.
Pertinent Anatomy
The disease primarily targets the striatum (caudate nucleus and putamen). Progressive caudate atrophy leads to the characteristic 'boxcar' ventricles seen on imaging.
Pathophysiology
Expansion of the polyglutamine tract leads to toxic gain-of-function of the huntingtin protein. This results in selective loss of GABAergic neurons in the striatum. The loss of inhibitory output leads to the hyperkinetic movements known as chorea.
Clinical Manifestations
Patients present with involuntary, jerky movements known as chorea, which may progress to rigidity. Psychiatric symptoms include depression, irritability, and personality changes. Suicide is a leading cause of death; monitor for impulsivity and psychosis.
Diagnosis
The genetic test for CAG repeat expansion is the gold standard. A threshold of >40 repeats is fully penetrant. MRI brain typically reveals atrophy of the caudate nucleus and putamen with secondary ventricular dilation.
Treatment
Tetrabenazine is the first-line agent for chorea by depleting dopamine. Reserpine is an alternative, but depression and suicidality are major side effects of VMAT2 inhibitors. Antipsychotics like haloperidol or olanzapine are used for severe behavioral symptoms.
Prognosis
The disease is universally fatal, with a mean survival of 15-20 years. Death is most commonly due to aspiration pneumonia or cardiovascular complications. Multidisciplinary care is required for end-of-life planning.
Differential Diagnosis
Sydenham chorea: associated with Group A Strep infection
Wilson disease: check ceruloplasmin and Kayser-Fleischer rings
Drug-induced dyskinesia: history of neuroleptic use
Neuroacanthocytosis: presence of acanthocytes on blood smear
Benign hereditary chorea: non-progressive course