Abstract:

Huntington’s disease is a devastating disorder that creates significant challenges for both patients and their families. It is inherited in an autosomal dominant manner and typically begins in mid-adulthood. The disease progresses gradually, leading to motor, cognitive, and behavioral problems. It is caused by a genetic mutation in the HTT gene, which results in the abnormal production of a protein called Huntingtin. This protein acts toxically and damages nerve cells, ultimately leading to their death.

Introduction:

What is Huntington (HD)?

Huntington’s disease, which was first extensively described by George Huntington in 1872, is the most common neurological disorder caused solely by a change in a single gene and it is more prevalent in developed countries such as those in Europe and North America. Huntington’s disease is inherited in an autosomal dominant pattern, meaning that only one copy of the mutated gene is needed for the disease to manifest. If an individual inherits one copy of the defective gene from either parent, the disease will be passed on, even if they receive a normal copy from the other. The disease typically begins in midlife and progresses continuously. Symptoms include movement, cognitive, and behavioral problems, significantly impacting the lives of both patients and their families. Huntington’s disease is caused by an excessive repetition of CAG triplets in the HTT gene. The HTT gene is responsible for producing a protein known as huntingtin. The increased number of CAG repeats causes the protein to be produced in an abnormal, elongated form, which damages nerve cells and leads to neurological disorders.

Symptoms:

In Huntington’s disease, the number of CAG repeats in the HTT gene determines the onset of symptoms. Initial symptoms include involuntary movements in the extremities and facial muscles, which progressively spread to the entire body. Key symptoms are irregular, jerky movements (chorea), difficulty speaking and swallowing, and reduced movement ability (hypokinesia). In advanced stages, muscle rigidity and abnormal contractions occur, leading to immobility and speech loss. Additionally, dystonia and tics may appear. Motor symptoms progressively impair daily activities, making tasks like dressing, cooking, and eating increasingly difficult. Psychiatric symptoms, including depression, anxiety, irritability, and obsessive-compulsive behaviors, often appear earlier and impact daily life. Depression is common, with feelings of guilt and weight loss. Suicide is more frequent in the early stages or as independence declines. In later stages, psychosis resembling schizophrenia can occur.

Effect on brain:

Huntington’s disease (HD) causes significant changes in the brain that progress over time. In this disease, the brain loses about 20 to 30 percent of its weight, and this amount may vary depending on the severity of the disease. The damage mainly occurs in a part of the brain called the “neostriatum”. This part receives information from the entire cortex and sends signals to areas like the “globus pallidus” and “substantia nigra”, which are two important parts of the brain that play a role in controlling movement and motor processes of the body. So, damage to these areas also has a significant impact on other parts of the brain.

Diagnose:

Huntington’s disease (HD) diagnosis is primarily based on clinical symptoms and the family history of an individual with a known affected parent. After taking a detailed history from the patient and reviewing the family history, the diagnosis is usually straightforward, unless the clinical picture is nonspecific or the parent is unknown. In such cases, medical records and autopsy reports may need to be reviewed. The gold standard for diagnosis is DNA testing, which shows a CAG repeat of at least 36 in the huntingtin gene.

Clinical criteria include motor changes along with psychiatric or cognitive changes, and in most cases, the combination of these three signs is sufficient for diagnosis. Imaging tests or general blood tests are not needed for diagnosis. However, informed consent from the patient is required for all diagnostic tests.

In differential diagnoses, when chorea (involuntary movements) is the primary symptom, taking the patient’s history is crucial. Many underlying internal disorders or iatrogenic causes (due to medications) can mimic HD. About 1% of cases diagnosed as HD clinically do not confirm the diagnosis with genetic testing; these are known as phenocopies.

Treatment:

The treatment of Huntington’s disease (HD) focuses on managing symptoms and improving quality of life, as there is still no definitive cure. Motor symptoms such as chorea are treated with drugs like tetrabenazine and olanzapine, while antiparkinsonian drugs used to treat hypokinetic symptoms have shown limited success. Currently, no medication is available to slow the progression of Huntington’s disease. In addition to pharmacological treatments, non-pharmacological care such as physiotherapy, occupational therapy, and psychological counseling plays a crucial role in patient management. In the advanced stages of the disease, 24-hour care and psychological support for caregivers become essential.

The Latest Advances in Promising Molecular Therapeutics for HD:

Research on Huntington’s Disease (HD) is advancing and focuses on the development of molecular and nonpharmacological therapies. Molecular approaches include genetic editing techniques like CRISPR/Cas9, reducing mutant proteins using RNAi and ASOs, and clearing harmful proteins with PROTACs.

Several drugs are also in various stages of clinical trials (phases 1, 2, and 3) to assess their safety and effectiveness. Additionally, observational studies like Enroll-HD examine brain and body changes associated with the disease, aiding in the design of preventive treatments.

Conclusion:

Huntington’s disease is a complex and progressive neurological disorder that has devastating effects on patients and their families. This disease, caused by a genetic mutation in the HTT gene, encompasses motor, cognitive, and psychiatric symptoms that gradually diminish an individual’s quality of life. Although there is no definitive cure for this condition, scientific advancements in molecular approaches and innovative treatments offer promising prospects. Current research, particularly in gene-editing techniques and the reduction of harmful proteins, highlights new pathways for managing the disease. Psychological support and non-pharmacological care also play a crucial role in improving the quality of life for patients and their families.

The future of research in this field, focusing on prevention and more effective treatments, holds the promise of reducing the impact of this disease on society.

Reference list:

Finkbeiner, S. (2011). Huntington’s Disease. Cold Spring Harbor Perspectives in Biology, [online] 3(6), pp.a007476–a007476 available at: https://cshperspectives.cshlp.org/content/3/6/a007476.full.pdf

Roos, R.A. (2010). Huntington’s disease: a clinical review. Orphanet Journal of Rare Diseases, [online] 5(1). available at: https://link.springer.com/content/pdf/10.1186/1750-1172-5-40.pdf

Waldvogel, H., H. Kim, E., J. Tippett, L., G. Vonsattel, J.-P. and LM Faull, R. (2014). The Neuropathology of Huntington’s Disease. [online] available at: https://www.researchgate.net/profile/HenryWaldvogel/publication/266744716_The_Neuropathology_of_Huntington%27s_Disease/links/54
72879a0cf2d67fc035c80a/The-Neuropathology-of-Huntingtons-Disease.pdf.

Written by:
Mahzad Tahaei