Journal of Dementia
Open Access

Huntington’s disease; Neurodegeneration; CAG repeat expansion; Mutant huntingtin; Striatal dysfunction; Cognitive decline; Psychiatric symptoms; Genetic basis; Molecular mechanisms; Therapeutic approaches; Disease modification; Neurobiology; Genetics

Introduction

Huntington’s disease (HD), also known as Huntington’s chorea, is a rare and devastating neurodegenerative disorder that affects the brain’s nerve cells, leading to progressive motor dysfunction, cognitive decline, and psychiatric symptoms [1]. Named after American physician George Huntington, who first described the disease in 1872, HD remains a challenging and complex condition with profound implications for affected individuals and their families. Huntington’s disease, first described by George Huntington in 1872, is a progressive and fatal neurodegenerative disorder that primarily affects the basal ganglia and cerebral cortex [2]. This devastating condition manifests in mid-adulthood, typically between the ages of 30 and 50, and steadily progresses over 15-20 years, resulting in severe physical and cognitive impairments. HD is inherited in an autosomal dominant manner, meaning that an individual with a single copy of the mutated gene from either parent will develop the disease [3]. The underlying genetic cause of Huntington’s disease lies in the expansion of CAG repeats in the HTT gene, located on the short arm of chromosome 4. While unaffected individuals typically have fewer than 35 CAG repeats, those with 40 or more repeats will invariably develop HD [4].

The mutated HTT gene encodes a polyglutamine expansion in the huntingtin protein, leading to the formation of aggregates within neurons. These aggregates disrupt cellular processes, impair axonal transport, and interfere with synaptic function [5]. The basal ganglia, a crucial region for motor coordination and control, is particularly affected, resulting in the characteristic motor symptoms of HD, including chorea, dystonia, and bradykinesia. As the disease progresses, cognitive decline becomes prominent, with individuals experiencing difficulties in memory, executive function, and emotional regulation. Psychiatric symptoms such as depression and anxiety are also common, adding to the complexity of the clinical picture [6].

Understanding the molecular and cellular mechanisms underlying Huntington’s disease is crucial for developing targeted therapies. Research has revealed disruptions in neurotransmitter systems, particularly involving dopamine and glutamate, as well as alterations in mitochondrial function and increased oxidative stress [7]. Inflammatory processes also play a role in the neurodegenerative cascade, further contributing to neuronal demise [8]. This review comprehensively examines the current state of knowledge regarding the pathophysiology of Huntington’s disease, highlights recent advancements in research, and explores potential therapeutic avenues for mitigating the devastating impact of this disorder on affected individuals and their families.

Genetic basis

Huntington’s disease has a unique genetic basis. It is caused by a mutation in the huntingtin (HTT) gene located on chromosome 4. This mutation involves an abnormal repetition of a specific DNA sequence known as CAG (cytosine-adenine-guanine). The greater the number of CAG repeats, the earlier the onset and severity of the disease. While a CAG repeat count of 10 to 35 is considered normal, individuals with 36 or more repeats may develop HD [9]. HD follows an autosomal dominant inheritance pattern, meaning that an individual needs only one copy of the mutated gene from either parent to develop the disease.

If a parent carries the mutated gene, each child has a 50% chance of inheriting it [10]. The onset of symptoms typically occurs in adulthood, with most individuals showing signs between the ages of 30 and 50. However, there are rare cases of juvenile-onset HD, where symptoms manifest before the age of 20.

Clinical manifestations: Huntington’s disease is characterized by a triad of symptoms encompassing motor dysfunction, cognitive decline, and psychiatric disturbances. Motor symptoms often include involuntary movements, known as chorea, which give the disease its alternate name. These movements can progress to more pronounced rigidity and bradykinesia, resembling features seen in Parkinson’s disease. Cognitive impairment involves difficulties with concentration, memory, and executive functions, significantly impacting daily life. Psychiatric symptoms include mood swings, depression, anxiety, and, in some cases, psychosis.

Neurological underpinnings: The pathological hallmark of Huntington’s disease is the progressive degeneration of specific brain regions, particularly the striatum, which plays a crucial role in motor control. As the disease advances, other areas such as the cortex and thalamus are also affected. The loss of neurons in these regions leads to the characteristic symptoms observed in individuals with HD.

The mutated huntingtin protein has toxic effects on neurons, disrupting cellular functions and triggering apoptotic pathways. It also interferes with the production and transport of neurotransmitters, further contributing to the breakdown of communication between nerve cells. Additionally, the formation of abnormal protein aggregates, known as inclusion bodies, is a prominent feature in the brains of individuals with HD.

Diagnostic challenges

Diagnosing Huntington’s disease can be challenging, especially in the early stages when symptoms may be subtle. Genetic testing for the presence of the mutated HTT gene is the most definitive method. However, given the ethical and emotional implications, individuals may choose not to undergo testing. Neuroimaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), can also aid in diagnosis by revealing characteristic changes in the brain.

Treatment and management: Currently, there is no cure for Huntington’s disease, and treatment primarily focuses on managing symptoms and improving the quality of life for affected individuals. Medications may be prescribed to alleviate motor symptoms, control psychiatric manifestations, and address cognitive decline. Physical and occupational therapy can help individuals maintain functional independence for as long as possible. Additionally, psychological support for both individuals with HD and their families is essential in coping with the emotional and practical challenges associated with the disease.

Research and future perspectives

The study of Huntington’s disease has advanced significantly in recent years, shedding light on the underlying molecular mechanisms and potential therapeutic targets. Gene-editing technologies, such as CRISPR-Cas9, hold promise for correcting the genetic mutation responsible for HD. Clinical trials are underway to explore the efficacy of various drugs in slowing the progression of the disease or alleviating its symptoms.

Conclusion

Huntington’s disease remains a formidable challenge for both researchers and healthcare professionals. As we deepen our understanding of the genetic and molecular underpinnings of HD, there is hope for the development of targeted therapies that may one day alter the course of this devastating disorder. In the meantime, providing comprehensive care and support for individuals with HD and their families is crucial in enhancing their quality of life and managing the complex challenges associated with the disease. Huntington’s disease (HD) stands as a formidable challenge in the realm of neurodegenerative disorders, casting a profound impact on the lives of individuals affected and their families. This complex genetic disorder, characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms, stems from an abnormal expansion of the CAG trinucleotide repeat in the huntingtin gene. As our understanding of the molecular mechanisms underlying HD advances, so too does the hope for therapeutic interventions that may one day mitigate its devastating effects.

The journey to conquer Huntington’s disease is an intricate tapestry woven with scientific discovery, technological innovation, and human resilience. While the road ahead may be challenging, the collective efforts of the scientific community and the unwavering determination of those affected by HD inspire optimism. As we stand on the precipice of a new era in neurodegenerative research, the hope persists that continued advancements will ultimately lead to breakthroughs in treatments and, ultimately, a cure for Huntington’s disease.

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