Huntington's disease and genetics
Huntington's disease is a fatal neurodegenerative disorder characterized by uncontrollable movements, cognitive decline, and psychiatric symptoms. First identified in 1872 by Dr. George Huntington, the disease results from the degeneration of neurons in specific brain regions, primarily the striatum and frontal cortex. It is inherited in an autosomal dominant manner through mutations in the huntingtin gene located on chromosome 4, which leads to the production of an abnormal protein that disrupts normal neuronal function. Individuals with a parent affected by the disease have a 50% chance of inheriting it, with the severity and age of onset often correlated with the number of CAG repeats in the gene. Symptoms typically manifest between ages 30 and 40 but can appear at any age.
No cure currently exists, and treatment focuses on alleviating symptoms, with new research exploring gene therapy and neuroprotective strategies. Screening for the genetic mutation is available, allowing individuals to understand their risk, though many opt against testing due to the emotional burden of the diagnosis. The disease predominantly affects individuals of European descent but is much rarer in other populations. As Huntington's disease progresses, it leads to significant physical and cognitive deterioration, ultimately resulting in death within 15 to 20 years of diagnosis.
Huntington's disease and genetics
DEFINITION Huntington’s disease is an incurable, fatal neurodegenerative disorder. Studying an extended New York family in 1872, Dr. George Huntington first documented this heritable malady that bears his name. Huntington’s disease was originally known as Huntington’s chorea because of its hallmark jerky involuntary movements (the term “chorea” comes from the Greek choros, meaning “dance”).
In Huntington’s disease, degeneration of neurons in specific brain regions occurs over time. Hardest hit is a particular subset of neurons in the striatum, a brain structure critical for movement control. Also affected is the frontal cortex, which is involved in cognitive processes. As the communication link between the striatum and cortex is broken through ongoing neuronal death, uncontrollable chorea, as well as intellectual and psychiatric symptoms, develop and worsen.
Risk Factors
An individual who has one parent with Huntington’s disease has a 50 percent chance of developing the disorder. In rare cases, individuals may develop the disease without a family history of the condition; this may be the result of a genetic mutation that occurred during their father’s sperm development. The disease is more prevalent in persons of European descent, affecting about one in ten thousand of these people, compared to fewer than one in one million people in African and Japanese populations.
Etiology and Genetics
Huntington’s disease is inherited as a dominant mutation of a gene located on the short arm of chromosome 4. The cloning of the HD gene in 1993 provided major impetus to understanding its function. The HD gene encodes a 348 kDa cytoplasmic protein called huntingtin. Normally, the HD gene contains a stretch of repeating triplets consisting of C (cytosine), A (adenine), and G (guanine). Healthy alleles contain anywhere from 9-35 CAG repeats. The CAG triplet encodes the glutamine; therefore, normal huntingtin contains a polyglutamine tract. Huntingtin is expressed throughout the brain (and indeed, the body); however, its regular function remains unclear. In neurons, huntingtin is thought to be important in counterbalancing programmed cell death by promoting the expression of growth factors. Huntingtin may therefore help protect striatal neurons throughout life.
Mutant alleles contain an expansion of the CAG repeat. The magnitude of this expansion can range from 36 to more than 60 CAG repeats (rarely, as many as 250 repeats have been observed). There is an inverse relationship between repeat number and age of disease onset: Higher repeat numbers are usually linked to younger onset. People with 36-39 CAG repeats may never show disease symptoms, whereas people with forty to sixty repeats usually develop Huntington’s disease in mid-adulthood, and those with more than sixty repeats often experience onset at less than twenty years of age.
Although original HD gene mutations clearly must occur, they are rare and of unknown cause. However, the HD gene’s inheritance patterns shed light on the mechanisms of CAG expansion. The gene exhibits genetic anticipation: Affected members of successive generations may show earlier onset, particularly when the pathogenic allele is inherited paternally. It is thought that occurs during the repair of DNA strand breaks, when CAG loops are retained in the nucleotide sequence during gap repair. If this happens in reproductive cells (particularly sperm), a larger CAG expansion will be present in the offspring.
The direct result of CAG expansion within the HD gene is that mutant huntingtin has a polyglutamine tract of variable but abnormally long length. Misfolding and aggregation of mutant huntingtin ensues. Cleavage of the mutant protein occurs, generating a fragment that can enter the nucleus. Visible cytoplasmic and nuclear huntingtin aggregates are a key pathological feature of the striatal neurons destined to die. This aggregation represents a different (albeit toxic) function for huntingtin. The aggregates contain not only mutant huntingtin but also several other critical proteins whose functions are effectively withheld. Because some of these sequestered proteins are transcription factors, transcriptional dysregulation may affect the expression of a host of additional proteins. In fact, the expression of huntingtin itself (from the remaining normal allele) is significantly reduced. This diminution of the availability of normal huntingtin may also contribute to neuronal demise. However, it is still unknown why only certain neurons die despite huntingtin’s ubiquitous expression.
Symptoms
The symptoms of Huntington’s disease include uncontrollable body movements and progressive dementia. Patients also experience marked cognitive and psychiatric decline. The onset is gradual and usually begins between ages thirty and forty, although symptoms can first appear within an age range of two to eighty years.
Screening and Diagnosis
The doctor will perform a physical exam, will ask about a patient’s family history and symptoms, and may also conduct a neurological exam. A computed tomography (CT) scan—a type of X-ray that uses a computer to take pictures of the structures inside the head—may detect loss of brain tissue. Other tests for Huntington’s disease include a magnetic resonance imaging (MRI) scan of the head and a positron emission tomography (PET) scan of the brain.
The cloning of the HD gene has enabled direct for the mutation. With a blood test, at-risk individuals can learn not only whether they carry the CAG expansion but also its length. Knowing one’s carrier status and predicted age of onset can eliminate doubt and assist in making life plans, but the prospect of developing a fatal disease can be far more stressful than the uncertainty. This may explain why a relatively low percentage of those with a family history of Huntington’s disease have opted to be tested. Whenever testing is performed, it is accompanied by extensive counseling both before and after the results are known.
Treatment and Therapy
Current treatments for Huntington’s disease are palliative and include antidepressants and sedatives. Strategies now under study are aimed at preventing CAG expansion, counteracting the toxic effects of mutant huntingtin, and delivering neuroprotective agents to the brain. Another tactic is to replace the dying striatal neurons with transplanted fetal neurons or stem cells. This approach has shown some promise: Following striatal grafts, few Huntington’s disease patients have experienced improvement in motor and cognitive function.
In 2024, researchers announced that treatment with high doses of uniQure's investigational gene therapy AMT-130 significantly slowed down the progression of Huntington's disease. uniQure, a gene therapy company, planned to present the findings to the Food and Drug Administration (FDA) later in the year.
Prevention and Outcomes
Huntington’s disease cannot be prevented and is incurable. The disease typically progresses to death within fifteen or twenty years of diagnosis.
Bibliography
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