Huntington Disease: Autosomal Dominant Genetic Disorder

Huntington Disease (HD)

• A rare neurodegenerative disease caused by a repeated sequence of DNA that leads to an abnormal protein formation, resulting in abnormal movements and cognitive problems.
• An autosomal dominant genetic disorder, meaning one affected copy of a gene is enough to cause disease.

Genetic Characteristics

• Typically, the gene called huntingtin or HTT on chromosome 4 contains a triplet repeat of C, A, and G nucleotides 10-35 times in a row.
• In people with HD, this repeat goes on for 36 or more times in a row.
• The CAG repeat codes for the amino acid glutamine, resulting in 36 or more glutamines in a row in the huntingtin protein.

Effects of HD

• The mutated protein aggregates within the neuronal cells of the caudate and putamen of the basal ganglia, causing neuronal cell death.
• Cell death might be related to excitotoxicity, which is excessive signaling of these neurons, leading to high intracellular calcium.

DNA Replication and Repeat Expansion

• The expanded CAG repeats affect DNA replication, causing DNA polymerase to lose track of which CAG it's on, resulting in extra CAGs being added.
• This expansion occurs during cell divisions, leading to ample opportunities for repeat expansion, making the gene more unstable.

Anticipation and Inheritance

• The phenomenon of anticipation means that HD families often show earlier symptom onset with each generation.
• Children of a parent with HD can inherit even more CAG repeats than the parent, leading to an earlier age of symptom onset.
• Repeat expansion occurs more in the production of sperm than eggs, resulting in anticipation and new disease alleles when the father is the affected parent.

Penetrance and Diagnosis

• A person with 40+ repeats shows 100% penetrance and will have the disease.
• People with 36-39 repeats can show reduced penetrance, with some having symptoms while others may not.
• The test for HD, which counts the number of CAG repeats, is effective in determining whether HD will develop in an at-risk individual.

Learn about Huntington disease, a rare neurodegenerative disorder that affects movement and cognition. Understand its genetic causes and inheritance patterns.