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Huntington’s Disease: A Comprehensive Review

Introduction

Huntington’s Disease (HD) is a rare, progressive, and inherited neurodegenerative disorder characterized by the gradual decline of motor control, cognitive abilities, and emotional stability. The disease is caused by a specific genetic mutation in the HTT gene and follows an autosomal dominant pattern of inheritance, which means that a child only needs to inherit one copy of the mutated gene from an affected parent to develop the disorder. This gives each child of an affected parent a 50% chance of inheriting the mutation.

HD is a lifelong condition that typically develops in adulthood, usually between 30 and 50 years of age, although juvenile forms may appear earlier. The disease progressively worsens over time and currently has no cure, ultimately leading to severe physical and mental disability. Treatment focuses mainly on symptom management and improving quality of life.

In this article, we will discuss Huntington’s Disease in detail, including its history, genetic basis, clinical presentation, diagnostic methods, pathophysiology, management strategies, prognosis, and ongoing research.

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Historical Background

Huntington’s Disease was first described in 1872 by Dr. George Huntington, an American physician. In his published report, “On Chorea,” he clearly outlined three major characteristics of the disorder:

1. Hereditary transmission
2. Adult onset
3. Progressive nature leading to severe disability

The disease was initially known as Huntington’s chorea due to the dance-like, involuntary movements (chorea) that patients exhibited. Over time, however, it became clear that HD is not merely a motor disorder but also involves cognitive decline and psychiatric symptoms. Thus, the name shifted from Huntington’s chorea to Huntington’s Disease to reflect its complex and multi-systemic nature.

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Genetic Basis and Inheritance

HTT Gene and CAG Repeat Expansion

The genetic cause of HD lies in a mutation in the HTT (Huntingtin) gene, located on chromosome 4p16.3. The mutation involves an abnormal expansion of a CAG trinucleotide repeat sequence within the gene.

• Normal: 10–35 CAG repeats
• Intermediate (mutable): 36–39 repeats (may or may not cause disease; can expand in offspring)
• Affected: ≥ 40 repeats (causes Huntington’s Disease)
• Juvenile onset: often > 60 repeats

The greater the number of repeated CAG sequences, the earlier and more severe the disease tends to be. This phenomenon is known as genetic anticipation, particularly common when the mutated gene is inherited from the father.

Autosomal Dominant Pattern

Since HD is autosomal dominant, a single mutated HTT gene is sufficient to cause the disease.

• Affected parent → each child has a 50% chance of inheriting the mutation.
• Individuals who do not inherit the mutation will never develop or pass on the disease.

This clear inheritance pattern makes genetic counseling and testing crucial in families with a history of HD.

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Pathophysiology

The Huntington protein, produced by the HTT gene, has important roles in brain development, neuronal survival, and cellular transport. The expanded CAG repeat causes the protein to become abnormally long and unstable, leading to misfolding and aggregation.

Key mechanisms involved:

1. Neuronal Degeneration: HD primarily affects the basal ganglia, especially the striatum (caudate nucleus and putamen), which is responsible for movement coordination and behavior regulation. Over time, cortical neurons also degenerate, leading to cognitive and personality changes.

2. Imbalance of Neurotransmitters:

   • Decreased GABA and acetylcholine
   • Relative excess of dopamine

   This imbalance contributes to choreiform movements and psychiatric symptoms.

3. Cellular Toxicity: Mutant huntingtin protein disrupts:

   • Mitochondrial function
   • Axonal transport
   • Transcription regulation
   • Synaptic communication

4. Brain Imaging Changes: MRI and CT scans show progressive atrophy of the caudate nucleus, enlarging the lateral ventricles.

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Clinical Features

HD affects motor, cognitive, and psychiatric functions. Symptoms progress slowly over 10–25 years.

1. Motor Symptoms

• Chorea: rapid, involuntary, jerky movements affecting limbs, face, and trunk.
• Dystonia: abnormal muscle contractions causing twisting postures.
• Bradykinesia: slowness of movement.
• Rigidity: especially in juvenile cases.
• Ataxia: poor balance and clumsiness.
• Dysarthria: difficulty speaking.
• Dysphagia: difficulty swallowing.
• Gait disturbance → frequent falls.

Over time, movements slow, and patients may become rigid and bedridden.

2. Cognitive Symptoms

HD causes progressive dementia.

• Difficulty planning and organizing tasks
• Impaired judgment
• Trouble learning new information
• Reduced concentration and memory
• Poor impulse control
• Loss of insight into behavior

Cognitive decline leads to complete dependence.

3. Psychiatric Symptoms

Psychiatric symptoms may precede motor symptoms by years.

• Depression (very common)
• Anxiety
• Irritability and aggression
• Obsessive-compulsive behaviors
• Bipolar disorder-like mood swings
• Psychosis (hallucinations, delusions)

Suicide risk is significantly increased.

Juvenile Huntington’s Disease

Onset before 20 years old. Symptoms differ:

• Rigidity > chorea
• Seizures common
• Rapid progression
• School decline and behavioral problems

Often associated with very high CAG repeat numbers.

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Stages of Disease Progression

1. Early Stage:

   • Mild chorea, subtle cognitive decline
   • Normal independence with slight difficulties

2. Middle Stage:

   • Worsening involuntary movements
   • Difficulty swallowing and speaking
   • Increasing dependence for daily activities

3. Late Stage:

   • Severe motor impairment (rigidity or inability to move)
   • Mutism
   • Dementia
   • Bedridden
   • Death typically occurs due to complications like pneumonia, falls, or malnutrition.

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Diagnosis

Clinical Assessment

• Family history
• Characteristic motor + cognitive + psychiatric signs

Genetic Testing

• Definitive diagnosis
• Blood test to count CAG repeats

Neuroimaging

• MRI/CT: Caudate and putamen atrophy
• PET scan: Reduced metabolic activity in basal ganglia

Neuropsychological Evaluation

• To assess cognitive impairment stage

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Management and Treatment

There is no cure, but treatments help manage symptoms and maintain quality of life.

1. Pharmacologic Treatment

Symptom	Medications	Mechanism
Chorea	Tetrabenazine, Deutetrabenazine	Reduces dopamine levels
Psychosis / Irritability	Antipsychotics (Risperidone, Olanzapine)	Dopamine blockade
Depression	SSRIs (Fluoxetine, Sertraline)	Serotonin modulation
Anxiety	Benzodiazepines	Calming effect
Mood Swings	Mood stabilizers (Valproate, Lithium)	Stabilizes emotions

2. Non-Pharmacologic Therapies

• Physical therapy → improves mobility and reduces falls
• Speech therapy → improves communication and swallowing strategies
• Occupational therapy → assists with daily activity adaptations
• Nutrition support → high-calorie diets required due to constant movement

3. Psychological and Social Support

• Counseling for patient and family
• Genetic counseling for relatives
• Support groups reduce stress and isolation

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Prognosis

• Average lifespan after symptom onset: 15–25 years
• Death usually occurs from:
  • Aspiration pneumonia
  • Malnutrition
  • Infections
  • Suicide

Earlier onset → faster progression.

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Recent and Emerging Research

Scientists are focusing on gene-targeted therapies:

1. RNA Interference and Antisense Oligonucleotides (ASOs):

   • Aim to reduce the production of mutant huntingtin protein.
   • Example: Tominersen (being tested in clinical trials).

2. Gene Editing (CRISPR-Cas9):

   • Proposed to correct the CAG expansion mutation.

3. Stem Cell Therapy:

   • Attempts to replace lost neurons.

4. Neuroprotective Agents:

   • Aim to preserve neuronal function and delay progression.

Though promising, most are still in research or early clinical trial phases.

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Conclusion

Huntington’s Disease is a devastating hereditary disorder that significantly impacts motor function, cognition, and emotional stability. Its roots lie in a well-defined genetic mutation, yet the complexities of its progression and systemic effects make it a challenging condition to manage. While there is currently no cure, advances in understanding the molecular basis of HD are opening pathways toward potential disease-modifying therapies and even curative approaches.

Comprehensive management through medication, therapy, psychological support, and family counseling can improve quality of life and ensure compassionate care for affected individuals. Continued research and increased public awareness remain essential for improving outcomes, supporting families, and moving closer to effective treatments or prevention strategies.

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