Huntington disease is a neurodegenerative disease that belongs to a category of genetic diseases known as trinucleotide repeat diseases. It’s a devastating disease clinically (patients develop relentlessly progressive motor and cognitive difficulties), and the unusual genetic features of the disease only add to the heartbreak, as we’ll discuss below.

Trinucleotide repeat disorders are diseases in which small, repetitive segments of DNA increase in number. Normally, there are some places in your DNA that have a few repeating sequences of three nucleotides. In trinucleotide repeat disorders like Huntington disease, these sequences expand in number (instead of, say, 35 repeats of a CAG sequence, you might have 50, or 60, or even 100). This genetic mutation leads to the production of an abnormal protein which is toxic to neurons.

One of the unusual, and awful, things about these diseases is that the number of repeats tends to increase with each generation (this is a phenomenon called anticipation). This means that grampa may have had 40 repeats, but your dad had 50, and now you have 60. Usually, the more repeats you have, the worse the disease is.

The main thing that happens in Huntington disease is neuronal damage and loss. An abnormal protein called Huntingtin protein (no, that’s not a typo, it really is Huntingtin protein with an “-in”) builds up in neurons, damaging and eventually killing them. This happens mostly in the basal ganglia (which modulates motor activity), and in the cortex.

The neurons that are hit the hardest are the spiny striatal neurons (in the caudate and putamen), which are neurons that dampen motor output. These neurons eventually simply disappear, effectively removing the brakes on motor control, causing patients to develop writhing (“choreoathetoid”) movements and interfering with normal motor activity. In addition to movement problems, patients also develop personality changes and cognitive deficits which eventually progress to severe dementia.

From a pathology perspective, the main things you see are atrophy and neuronal loss. The entire brain undergoes atrophy, but the most pronounced changes are seen in the caudate nucleus and frontal lobe. In the image above, the patient has gross atrophy of the brain and markedly atrophic caudate nuclei. The caudate nuclei should bulge into the ventricles – but in this patient, you can barely see them (they are the small, dark, flat strips on the sides of the ventricles). The ventricles are enlarged as result of the loss of brain mass (a condition called hydrocephalus ex vacuo).

Microscopically, the caudate nuclei show loss of the spiny neurons we talked about above. They just drop out! Eventually the putamen and the cortex show neuronal loss too.

I think the best way to put this all together in a meaningful way is to read about patients who have the disease. This New York Times article is excellent (and very sad). It discusses not only the disease itself, but the conundrum faced by people who have a family history of the disease: should I get genetic testing or not?