USMLE® Step 1 style questions USMLE
A 39-year-old woman is brought to the clinic by her partner for involuntary movements of the hands and face. The symptoms began 6-months ago and have progressively worsened. In addition, she has been experiencing personality changes over the past 2 months. According to the partner, the patient has withdrawn from activities she previously enjoyed, such as attending weekly book clubs with her friends. Moreover, the patient has had a decreased appetite and is sleeping less than before. Past medical history is noncontributory. Her father experienced similar motor symptoms and commited suicide at the age of 47. In the office, her temperature is 37.0°C (98.6°F), pulse is 78/min, blood pressure is 126/80 mmHg, and respirations are 14/min. Deep tendon reflexes are 3+ bilaterally in the upper and lower extremities. During the physical exam, the patient makes repeated writhing movements using the fingers and arms. Imaging of the head is ordered. MRI of the brain is most likely to demonstrate which of the following?
Huntington disease, or HD, is a rare neurodegenerative disease that involves a repeated sequence of DNA that causes an abnormal protein to form, leading to abnormal movements and cognitive problems.
Huntington disease is an autosomal dominant genetic disorder, which means that one affected copy of a gene is enough to cause disease.
Affected people are typically present in each generation, because an affected person (male or female) has a 50% chance of passing on the affected gene to a child, which causes that child to have the disease.
In most people, a gene called huntingtin or HTT on chromosome 4, contains a triplet repeat, where the nucleotides C, A, and G are repeated 10-35 times in a row.
In people with Huntington disease, this repeat goes on for 36 or more times in a row.
CAG codes for the amino acid glutamine, so people with Huntington disease patients will have 36 or more glutamines in a row in the huntingtin protein.
So, in addition to being a triplet repeat disorder, HD is, more specifically, a “polyglutamine” disease.
The specific way in which extra glutamines causes HD symptoms isn’t fully worked out, but some clues are that 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, which leads to high intracellular calcium.
The expanded CAG repeats not only affect the huntingtin protein – they affect DNA replication itself.
When copying the HTT gene, DNA polymerase can basically lose track of which CAG it’s on and accidently add extra CAGs.
Since as a zygote develops into a fetus and eventually into a full adult, by the time sperm and eggs are created, several dozen cell divisions, each with a round of DNA replication have taken place, and so there have already been ample opportunities for repeat expansion, and the more repeats that’re added, the more unstable it gets.
This expansion of the originally inherited gene means a child of a parent with HD can inherit even more CAG repeats than the parent did.
The higher the number of repeats in the protein, the earlier the age when a person starts having symptoms.
This phenomenon is called anticipation, which means that Huntington disease families often show earlier symptom onset with each generation.
Even repeats of 27-35 CAGs can expand occasionally; these are called “pre-mutation” alleles, since they don’t cause the disease, but they’re set-up for developing a mutation of 36 or more CAGs.