Huntington's Disease | How Can a Single Gene Cause Such Profound Changes in the Brain?

Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by a mutation in a single gene, called Huntingtin (HTT). Neurodegenerative means that it causes the progressive breakdown and death of nerve cells, or neurons, in the brain. The mutation involves an expansion of a specific DNA sequence known as a CAG (cytosine-adenine-guanine) trinucleotide repeat. In a healthy individual, the HTT gene contains a certain number of these CAG repeats. However, in individuals with HD, this sequence is repeated an excessive number of times. This expanded repeat leads to the production of an abnormal huntingtin protein that is toxic to neurons, particularly in brain regions responsible for movement, thought, and emotion, such as the basal ganglia and cerebral cortex. The inheritance pattern is autosomal dominant, which means that an individual needs only one copy of the mutated gene from one parent to develop the disease. Consequently, a child of an affected parent has a 50% probability of inheriting the gene and developing the disorder. The length of the CAG repeat expansion is inversely correlated with the age of onset; a higher number of repeats typically leads to an earlier onset of symptoms and potentially a faster progression of the disease.

The primary distinction between adult-onset and juvenile-onset Huntington's Disease lies in the age at which symptoms first appear and the nature of those initial symptoms. Adult-onset HD is the most common form, typically manifesting in a person's 30s or 40s. It often begins with subtle changes in mood, coordination, and cognitive function, which gradually progress to more severe motor impairments, most notably chorea—involuntary, jerky, and dance-like movements. In contrast, juvenile-onset HD is rare, appearing before the age of 20. It is frequently associated with a very large number of CAG repeats, often inherited from the father. The initial symptoms in juvenile HD can be different from the adult form and may include stiffness and rigidity (akinesia), clumsiness, a decline in school performance, and seizures. Chorea is less common in the early stages of juvenile HD. The progression of juvenile HD is also typically faster and more severe than the adult-onset form.

The symptoms of Huntington's Disease are generally categorized into three main areas: motor, cognitive, and psychiatric. Motor symptoms are the most visible and include chorea (the involuntary, writhing movements), dystonia (sustained muscle contractions causing twisting), and problems with balance and coordination. As the disease progresses, voluntary movements become increasingly difficult, affecting walking, speaking, and swallowing. Cognitive symptoms involve a decline in the ability to think, plan, and organize. This includes memory lapses, difficulty concentrating, and impaired judgment. Psychiatric symptoms are also very common and can appear even before motor disturbances. These include depression, anxiety, irritability, apathy, and, in some cases, psychosis. These symptoms result from the progressive deterioration of neurons in specific brain areas.

The diagnosis of Huntington's Disease is a multi-step process. It begins with a thorough clinical evaluation, including a review of the patient's personal and family medical history. A neurologist will perform physical and neurological examinations to assess for characteristic motor symptoms like chorea, as well as cognitive and psychiatric changes. Brain imaging techniques, such as MRI or CT scans, may be used to look for characteristic changes, like atrophy (shrinkage) in the basal ganglia. However, the definitive diagnosis is made through genetic testing. A blood sample is analyzed to count the number of CAG repeats in the HTT gene. An expansion of 40 or more repeats confirms the diagnosis of HD. Predictive testing is also available for asymptomatic individuals with a family history of the disease to determine if they carry the mutated gene.

Currently, there is no cure for Huntington's Disease, nor is there any treatment that can halt or reverse the progressive neurodegeneration it causes. However, medical management focuses on alleviating symptoms and improving the quality of life for patients. Pharmacological treatments are available to manage some of the most disruptive symptoms. For instance, medications like tetrabenazine and deutetrabenazine can help suppress chorea. Antidepressants, antipsychotics, and mood-stabilizing drugs may be prescribed to address the psychiatric symptoms. Beyond medication, a comprehensive, multidisciplinary approach is crucial. Physical therapy helps with balance, strength, and flexibility, while occupational therapy assists patients in adapting their daily activities and environment to maintain independence for as long as possible. Speech-language therapy is also vital for addressing difficulties with communication and swallowing. Ongoing research into gene-silencing therapies and other novel approaches offers hope for more effective treatments in the future.