Huntington's disease

Huntington's disease is a progressive, fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. This genetic mutation leads to the production of a mutant form of the huntingtin protein, which gradually damages neurons in the brain, particularly within the basal ganglia and cerebral cortex. The condition is characterized by a triad of movement disorders, cognitive decline, and psychiatric symptoms, with onset typically occurring in mid-adulthood. As an autosomal dominant disorder, each child of an affected parent has a 50% chance of inheriting the disease-causing allele.

Signs and symptoms

The clinical presentation classically involves a combination of motor, cognitive, and psychiatric disturbances. The most recognizable motor feature is chorea—involuntary, jerky, dance-like movements—though dystonia, bradykinesia, and impaired gait are also common. Cognitive symptoms often begin with executive dysfunction, progressing to dementia and severe cognitive impairment. Psychiatric manifestations are highly variable and can include depression, apathy, irritability, obsessive-compulsive behavior, and psychosis. Other complications include significant weight loss, dysphagia leading to aspiration pneumonia, and an increased risk of suicide.

Genetics

The disorder is caused by an expanded trinucleotide repeat (CAG) in exon 1 of the HTT gene located on chromosome 4. This mutation is a dynamic mutation, with the number of repeats often increasing during gametogenesis, a phenomenon known as anticipation. Individuals with 40 or more CAG repeats will invariably develop the disease, while those with 36–39 repeats may exhibit reduced penetrance. The allele is autosomal dominant, meaning a single copy of the mutated gene from either parent is sufficient to cause the disorder. Genetic counseling is a critical component of care for at-risk individuals and families.

Pathophysiology

The expanded CAG repeat in the HTT gene is translated into an elongated polyglutamine tract within the huntingtin protein. This mutant protein is prone to misfolding and forms toxic aggregates inside neurons, particularly affecting the striatum and cerebral cortex. These aggregates are thought to disrupt vital cellular processes, including transcription, mitochondrial function, and axonal transport. The resulting neurodegeneration leads to severe atrophy of the caudate nucleus and putamen, which correlates with the progressive motor and cognitive symptoms observed clinically.

Diagnosis

Diagnosis is primarily confirmed through genetic testing to detect the CAG repeat expansion in the HTT gene. This testing is typically preceded by a detailed clinical examination by a neurologist and a thorough family history. Neuroimaging studies, such as MRI or CT scan, often reveal characteristic atrophy of the caudate nuclei and generalized cortical atrophy. Differential diagnosis includes other causes of chorea, such as Sydenham's chorea, neuroacanthocytosis, and Wilson's disease.

Management

There is no cure, so management focuses on symptomatic treatment and multidisciplinary care. Movement disorders may be managed with medications like tetrabenazine or deutetrabenazine, which are Vesicular monoamine transporter 2 inhibitors. Antipsychotics such as haloperidol or risperidone can help control chorea and psychiatric symptoms, while antidepressants are used for mood disorders. Non-pharmacological support includes physical therapy, occupational therapy, speech-language pathology, and nutritional support. Ongoing clinical trials are investigating novel approaches, including gene silencing therapies like tominersen.

Epidemiology and history

The prevalence is estimated at 5–10 cases per 100,000 people of European descent, with lower rates in other populations such as Japanese and African populations. The disorder was first described in modern medical literature by George Huntington in 1872 in his paper "On Chorea," presented at the Meigs and Mason Academy of Medicine in Ohio. Important research milestones include the establishment of the Hereditary Disease Foundation by Milton Wexler, the linkage analysis locating the gene to chromosome 4 in 1983 by the United States–Venezuela Collaborative Research Project, and the definitive identification of the HTT gene by the Huntington's Disease Collaborative Research Group in 1993. Category:Genetic disorders Category:Neurodegenerative disorders Category:Autosomal dominant disorders