No chorea in Huntington’s linked to fewer CAG repeats in HTT gene

Lack of key symptom may delay diagnosis, even with cognitive problems

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People carrying fewer Huntington’s disease-causing CAG repeats in the HTT gene — who traditionally are thought to have milder disease — show similar cognitive deficits to those with more CAG repeats, a study found.

However, patients with fewer repeats are less likely to show Huntington’s characteristic involuntary muscle contractions, or chorea, and take longer to be diagnosed than those with more CAG repeats.

This suggests that, despite the presence of cognitive impairment, the absence of chorea may delay a Huntington’s diagnosis in carriers with fewer CAG repeats.

“This finding should encourage neurologists to consider Huntington’s disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring,” the researchers wrote.

The study, “Huntington’s Disease with Small CAG Repeat Expansions,” was published by a team of researchers in France and Italy in the journal Movement Disorders.

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Investigating the impact of CAG repeats on Huntington’s symptoms

Huntington’s is caused by excessive repeats of three DNA building blocks — C, A, and G — in the HTT gene, which codes for a protein called huntingtin that’s thought to help nerve cells develop.

A healthy HTT gene contains 10-35 repeats. A greater number of repeats results in the production of an abnormally long huntingtin protein, which can be toxic to nerve cells and lead to symptoms such as chorea, and cognitive and emotional problems.

People who carry 40 CAG repeats or more almost always develop Huntington’s, while those with less than 39 repeats may or may not develop the neurodegenerative disorder. When they do, it’s thought that their symptoms may be milder.

To investigate whether this is true, a team of researchers compared data from people carrying 36-38 CAG repeats with individuals with a greater number of repeats. Both groups included people already diagnosed with Huntington’s and those not yet showing symptoms.

The team first looked at 35 French people who carried a lower number of CAG repeats — most commonly 38 (42.9%). The 17 of them who did not manifest any symptoms were, on average, 21 years younger than the 18 who did (43.2 vs. 64.2 years). During follow-up, five of the 17 began showing symptoms too, totaling 23 people with manifest Huntington’s.

At their first visit, all 18 of these Huntington’s patients experienced movement problems that were worsen than at their previous visit. Also, nearly one-third of the patients who at some point showed symptoms — 30.4%, or seven of the 23 — did not experience chorea.

Other movement problems “were mostly discrete and variable,” the researchers wrote. These included eye issues, spasms, and difficulty with coordination and maintaining posture.

More than half of all the patients (51.4%) experienced behavior problems and had psychiatric symptoms or a history of psychiatric issues. Also, more than 90% of a total 23 people who underwent a cognitive evaluation were found to be cognitively impaired.

The researchers then compared the cognitive data from 11 of these individuals with an equal number of age- and sex-matched patients, each of whom had 40-42 CAG repeats. Contrary to what the team expected, the cognitive impairment of those who carried fewer CAG repeats was not milder.

In fact, “the cognitive and psychiatric profile was very similar with no significant differences in the domains of global cognitive efficiency, executive functioning, processing speed, emotional recognition, and frequency of psychiatric symptoms (90.9% in both groups),” the researchers wrote.

Executive functioning refers to a set of cognitive processes involved in planning and decision-making. Processing speed, meanwhile, reflects the time it takes a person to process information, whereas emotional recognition is the ability to recognize emotions in others.

As expected, those carrying fewer repeats scored about half as much in the motor part of the Unified Huntington’s Disease Rating Scale (UHDRS; 16.4 vs. 34.2 points), meaning that their symptoms were less severe. However, these patients were nearly twice less likely to experience chorea as their first symptom (54.4% vs. 100%).

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Doctors less confident in making Huntington’s diagnosis

To confirm their findings, the researchers looked at data from a larger group of 235 people who carried 36-38 CAG repeats. The team compared them with 4,675 people with more repeats —ranging from 39 to 46 — who were taking part in Enroll-HD (NCT01574053), the world’s largest observational study of Huntington’s, which is ongoing.

The results from these patients matched those seen in the first, smaller group. People with fewer CAG repeats had a similar cognitive profile to those with more CAG repeats but less frequent chorea despite similar UHDRS motor scores.

Importantly, the researchers found that doctors were significantly less confident in making a diagnosis of Huntington’s in people with 36-38 CAG repeats. Consistently, these people had to wait significantly longer — by about one year — for a diagnosis compared with those with 40-42 CAG repeats.

The delay occurred despite a similar mean age at symptom onset across the groups (54.3 vs. 53.9 years).

According to the researchers, this may be due to the absence of chorea rather than having milder symptoms.

[Huntington’s disease] should be considered in patients with unexplained cognitive decline including impaired episodic memory, even in the absence of typical motor symptoms or family history.

These findings highlight that carriers of 36-38 CAG repeats “are as severely affected by disease as patients with larger, but still moderate expansions,” the researchers wrote, adding that “they present with less chorea resulting in a greater delay and less confidence in the diagnosis of manifest HD [Huntington’s disease].”

“In conclusion, HD should be considered in patients with unexplained cognitive decline including impaired episodic memory, even in the absence of typical motor symptoms or family history,” the team concluded.