Huntington’s disease (HD) is a progressive, inherited neurodegenerative disorder that gradually affects a person’s movement, thinking abilities, and mental health. This condition leads to the loss of functional capacity over many years. Understanding the disease involves recognizing the specific functional milestones that define its progression through five distinct clinical stages.
Genetic and Molecular Basis of Huntington’s Disease
Huntington’s disease is caused by a defect within the HTT gene, located on chromosome 4. This gene provides instructions for making the huntingtin protein, which is especially active in the brain’s nerve cells (neurons). The disease results from a change in the HTT gene that includes a repeated segment of DNA known as the CAG trinucleotide repeat expansion.
The CAG segment codes for the amino acid glutamine and is repeated an abnormally high number of times in people with HD. While unaffected individuals typically have 10 to 26 CAG repeats, 40 or more repeats almost always result in HD development. This excess repetition leads to the production of a toxic, abnormally long version of the huntingtin protein.
The mutant huntingtin protein is cut into smaller, damaging fragments that accumulate inside neurons. This buildup disrupts normal cell functions, causing them to become dysfunctional and eventually die. The brain regions most affected are the striatum and the cerebral cortex, which coordinate movement, thought, and emotion. The loss of neurons in these areas underpins the physical, cognitive, and psychiatric symptoms of the disease.
The Five Stages of HD Progression
The progression of Huntington’s disease is described using a five-stage system focused on the patient’s Total Functional Capacity (TFC) and ability to live independently. This framework tracks the disease as it moves from subtle changes to a state of complete dependence.
Stage 1: Pre-Manifest and Early Motor Onset
This initial stage occurs before classic motor symptoms are obvious enough for a formal diagnosis. Individuals may experience subtle changes in mood, such as depression or irritability, and minor cognitive difficulties with complex problem-solving. Although mild involuntary movements or coordination problems may exist, the person remains fully functional and can continue to work, drive, and manage finances independently. The TFC score is the highest (11 to 13), reflecting minimal impairment of daily activities.
Stage 2: Early-Intermediate Decline
Symptoms become noticeable enough in this stage to warrant a formal HD diagnosis. Involuntary movements (chorea) become more apparent, and coordination issues result in clumsiness and stumbling. Individuals can still manage most self-care activities but may require slight assistance with complex tasks like domestic or financial affairs. The person is typically unable to maintain employment or drive safely, and the TFC score drops to a range of 7 to 10.
Stage 3: Late-Intermediate Impairment
This stage is defined by a significant loss of independence as symptoms become severe and debilitating. Individuals require major assistance with most basic functions, including domestic chores and financial management. Motor symptoms progress, leading to increasing difficulty with voluntary movements, balance, and frequent falls. Swallowing difficulties and slurring of speech frequently emerge, and cognitive problems impair the ability to learn new information or remember details. The TFC score ranges from 3 to 6, indicating substantial reliance on others for daily care.
Stage 4: Early-Advanced Deterioration
This stage represents a near-total dependence on others for all activities of daily living. Motor control worsens, and involuntary movements often become severe. In some cases, chorea may lessen and be replaced by rigidity and slowness of movement (bradykinesia). Communication struggles intensify due to severe speech problems, and the TFC score typically falls to 1 or 2.
Stage 5: Late-Advanced Dependence
The final stage of HD is characterized by complete dependence for all care. Individuals are often non-verbal, bedridden, and require full-time skilled nursing care. The inability to safely swallow may necessitate the use of a feeding tube for nutritional support. Motor symptoms are dominated by rigidity, bradykinesia, and involuntary muscle contractions, though patients may still retain some level of understanding and awareness. The TFC score in this stage is zero, reflecting the complete loss of functional capacity.
Comprehensive Symptom Management Strategies
While no treatment can slow or stop the underlying progression of HD, symptomatic management is the primary focus of care to improve quality of life. Treatment involves a multidisciplinary approach combining pharmacological agents with non-pharmacological support mechanisms.
Pharmacological interventions are tailored to target motor, cognitive, and psychiatric symptoms. For the involuntary movements of chorea, VMAT2 inhibitors (such as valbenazine and deutetrabenazine) are used to deplete central monoamines and reduce movement severity. Psychiatric symptoms like depression, anxiety, and irritability are commonly managed with selective serotonin reuptake inhibitors (SSRIs) or other antidepressants, sometimes combined with mood stabilizers. Atypical antipsychotic medications may be prescribed for hallucinations or delusions, often preferring newer agents due to a lower risk of side effects.
Non-pharmacological strategies are important for maintaining function and independence. Physical and occupational therapies address gait instability, motor skill decline, and safety by focusing on balance training and home modifications. Speech-language pathologists manage communication difficulties and swallowing problems, which reduces the risk of aspiration and maintains adequate nutrition.
Nutritional support is necessary because involuntary movements can cause significant weight loss. Dietitians may recommend high-calorie diets or liquid supplements. Cognitive behavioral therapy (CBT) and other psychological supports are beneficial for managing mood changes, depression, and anxiety, complementing the effects of medication. Establishing a regular daily routine helps compensate for memory and organizational difficulties throughout the disease course.