Huntington disease (Year of the Zebra)

Summary

Huntington's disease (HD) is a rare, inherited neurodegenerative disorder caused by abnormal CAG repeats in the HTT gene, leading to a defective protein. This results in progressive motor, cognitive, and psychiatric symptoms. HD is autosomal dominant, with a 50% chance of passing it to offspring. More CAG repeats cause earlier onset, a phenomenon known as anticipation. HD primarily affects neurons in the basal ganglia, leading to abnormal movements like chorea, and mental symptoms such as dementia. Although treatments manage symptoms, there is no cure, and life expectancy post-diagnosis is 10-20 years.

Takeaways

• 🧠 Huntington disease (HD) is a rare, neurodegenerative disorder caused by a repeated DNA sequence, leading to abnormal protein formation, affecting movement and cognition.
• 🧬 HD is an autosomal dominant genetic disorder, meaning a single copy of the mutated gene is enough to cause the disease, with a 50% chance of being passed to offspring.
• 🧪 The disease is caused by a CAG triplet repeat in the HTT gene on chromosome 4. In people with HD, the CAG sequence is repeated 36 or more times.
• 🔬 HD is a polyglutamine disease, where excess glutamines in the Huntington protein lead to symptoms, though the exact mechanism is not fully understood.
• 💀 Neuronal cell death occurs in the caudate and putamen of the basal ganglia, possibly due to excitotoxicity, leading to motor and cognitive symptoms.
• 📈 The more CAG repeats present, the earlier symptoms begin. This phenomenon, called anticipation, often results in earlier onset in each generation.
• 🧓 HD primarily affects movement, causing symptoms like chorea (jerky movements) and athetosis (slow, writhing movements), along with cognitive decline and personality changes.
• 🔍 Diagnosis is based on clinical assessment and confirmed with genetic testing, with imaging like MRI or CT used to evaluate brain atrophy.
• 💊 Treatments, including neuroleptics and tetrabenazine, can help manage symptoms but do not extend survival. Most patients die within 10-20 years from complications like pneumonia or suicide.
• 🔁 HD is part of a group of triplet repeat disorders, including myotonic dystrophy, ataxia, and fragile X syndrome, which involve different nucleotide repeats.

Q & A

What is Huntington disease (HD) and how does it affect the body?

Huntington disease (HD) is a rare neurodegenerative disorder caused by a repeated sequence of DNA that results in an abnormal protein. This leads to progressive central nervous system disturbances, including abnormal movements and cognitive problems.

How is Huntington disease inherited?

Huntington disease is inherited in an autosomal dominant manner, meaning one affected copy of the gene is enough to cause the disease. An affected person has a 50% chance of passing the gene to their child.

What is the role of the CAG repeat in Huntington disease?

In HD, the gene called HTT on chromosome 4 contains a triplet repeat of the nucleotides CAG. Normally, this sequence is repeated 10-35 times, but in HD patients, it repeats 36 or more times, leading to the production of an abnormal Huntington protein.

What is anticipation in the context of Huntington disease?

Anticipation refers to the phenomenon where the number of CAG repeats increases with each generation, leading to earlier symptom onset in affected individuals.

How do CAG repeats affect DNA replication and inheritance?

The CAG repeats can expand during DNA replication, particularly in sperm cells, leading to an increase in the number of repeats. This can cause a child to inherit more CAG repeats than their parent, resulting in earlier onset of Huntington disease.

What are the main symptoms of Huntington disease?

Huntington disease causes progressive movement issues like chorea (dance-like movements) and athetosis (snake-like writhing), cognitive decline, mood disturbances, and psychological issues such as depression and dementia.

How is Huntington disease diagnosed?

HD is diagnosed based on a patient's history, physical examination, and genetic testing to count the number of CAG repeats. Brain imaging techniques like CT scans or MRIs can be used to assess brain tissue atrophy.

Why do treatments for Huntington disease not improve overall survival?

Although treatments like neuroleptics and tetrabenazine help manage symptoms such as chorea, they do not slow down the progression of the disease or improve overall survival. Death often occurs within 10-20 years of diagnosis due to complications like aspiration pneumonia or suicide.

What is the significance of GABA, acetylcholine, and dopamine levels in Huntington disease?

In Huntington disease, levels of GABA and acetylcholine decrease, while dopamine levels increase in affected brain regions. This helps explain why dopamine-depleting drugs and dopamine receptor antagonists are used to manage symptoms.

Are there other diseases similar to Huntington disease in terms of genetic repeats?

Yes, there are several other triplet repeat disorders, including myotonic dystrophy (CTG repeat), Friedreich's ataxia (GAA repeat), and fragile X syndrome (CGG repeat). Each has different genetic mutations but shares the characteristic of nucleotide repeat expansion.