- Huntington’s disease (HD) is a rare, inherited neurodegenerative disorder characterized by a progressive breakdown of nerve cells in the brain, leading to motor dysfunction, cognitive decline, and psychiatric disturbances.
- It is an autosomal dominant disorder, meaning a single copy of the mutated gene from an affected parent is sufficient to cause the disease. The genetic mutation responsible for HD is an expansion of CAG trinucleotide repeats in the HTT gene located on chromosome 4, which encodes the protein huntingtin. In affected individuals, the excessive repetition of the CAG sequence results in an abnormally long polyglutamine tract in the huntingtin protein, causing it to misfold, aggregate, and become toxic to neurons.
- The hallmark signs of Huntington’s disease typically emerge in mid-adulthood, between the ages of 30 and 50, although juvenile-onset and late-onset forms also exist. The clinical triad of symptoms includes movement disorders, cognitive impairment, and psychiatric disturbances. The most recognizable motor symptom is chorea, a pattern of involuntary, rapid, and unpredictable jerking movements affecting the face, limbs, and trunk. As the disease advances, chorea may be replaced by rigidity and bradykinesia, resembling features of Parkinsonism. Impaired coordination, difficulty with speech and swallowing (dysphagia), and frequent falls also develop with disease progression.
- Cognitive symptoms of HD typically begin with difficulties in executive functioning, such as planning, organizing, multitasking, and maintaining attention. As the disease progresses, these deficits worsen, eventually leading to dementia. Memory is often relatively preserved in early stages but deteriorates in later stages of the disease.
- Psychiatric symptoms are prominent and can be the first manifestation in some individuals. These include depression, irritability, anxiety, apathy, obsessive-compulsive behaviors, and in some cases, psychosis. Suicidal ideation and behaviors are of particular concern in HD and require proactive management.
- The diagnosis of Huntington’s disease is confirmed through genetic testing, which identifies the number of CAG repeats in the HTT gene. A repeat count of 36 or more is generally diagnostic, with longer expansions associated with earlier onset and more severe disease. Individuals with 40 or more repeats almost always develop symptoms during their lifetime.
- There is currently no cure for Huntington’s disease, and treatment is aimed at managing symptoms and improving quality of life. Tetrabenazine and deutetrabenazine are approved for treating chorea by depleting dopamine, but they can worsen depression. Antipsychotic drugs and antidepressants are commonly used to manage psychiatric symptoms. Physical, occupational, and speech therapy are crucial components of supportive care. Nutritional support becomes increasingly important as the disease advances and patients have difficulty eating and maintaining weight.
- The course of Huntington’s disease is progressive and ultimately fatal, with life expectancy typically ranging from 15 to 20 years after onset. Death often results from complications such as aspiration pneumonia, infections, or injuries from falls.
