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Testing, or at risk Discuss testing for Huntington’s disease, and living with the risk of HD

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Old 12-10-17, 12:38 AM   #1
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Location: Hastings, East Sussex, UK
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Default Does a higher CAG Repeat Count mean an earlier age of onset?

Originally Posted by Mrsmcgee - in other threads.
Hello all I'm Ashleigh. My man passed away with hd at the age of 40. After suffering for 14 years. I've been tested and do have the gene myself. I'm just wondering weather a higher cag count means an earlier age of oneset. Thanks.

Hi Ashleigh so sorry about your mum and also your positive status. it is believed a higher count means an earlier onset but its not exact and there is such a range difference within the CAG of when onset occurs .Do you see a neurologist maybe speak to them . Are you concerned you may have symptoms are your nearing your mums age of Onset ?.


Hi Ashleigh
As this is such a major topic I thought I'd replace it in this category and a new thread if you don't mind. Big issues sometimes get "lost" or quickly hidden on the Message Board.

If you asked your question in HD Facebook groups then you’d most likely get the answer “Yes”. That generally seems to be from personal and family situations. The science probably tells a different story - but it’s quite difficult to get your head around ... and, of course, it might not be all correct.

It’s the same old story: head or heart - as to how you interpret it from social media and forums such as this. The research certainly doesn’t give a picture of full clarity. So, as Gabby suggests you probably need to see a Neurologist who specialises in degenerative diseases, and Huntington’s Disease in particular, in order to get your question answered.

This is some of the CAG related research. I've tried to reduce it without losing its meaning and impact:

Huntington’s Disease Genetics

HD is a “trinucleotide repeat” disorder, which is caused by an increase in the number of CAG repeats in the HD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendants. Repeats of 36-39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing.

HD is a dominantly transmitted neurodegenerative disorder involving the basal ganglia and cerebral cortex that typically strikes in midlife but can occur as young as age 2 or 3 and as old as age 80 or more. Survival from onset to death averages 17–20 years with some evidence that later onset is associated with slower progression.

although the correlation between repeat size and onset age is strong, it is widely acknowledged that the repeat size is a poor predictor of onset age. The predictive shortcomings can be appreciated by examining the range of onset age for persons with a particular number of repeats.

For example, people with 44 CAG repeats have exhibited onset ages as young as 31 and as old as 66 years of age. The 34-year span in onset demonstrates not only the poor predictive power for onset of the repeat size, but also the substantial variation in onset age that is not explained by the HD repeat. It is important therefore to recognize that predictive HD gene testing will not reveal meaningful information about when an individual is likely to develop symptoms of the illness and this should be made clear in pre-test counselling.

CAG-Repeat Length and the Age of Onset in Huntington Disease (HD): A Review and Validation Study of Statistical Approaches [2010]

Almost immediately upon discovery of this gene, it was recognized that the mean age of clinical onset was strongly related to length of the CAG trinucleotide expansion that codes for the polyglutamine repeat. Since then, numerous statistical models have been published that fit relationships between CAG length and clinical onset.

I’m listing the following research papers for anyone specifically interested in the Genetic Science around CAG Repeat Length. If you can fathom it out …

Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease

Differences in duration of Huntington’s disease based on age at onset

Huntington’s disease age-of-onset linked to polyglutamine aggregation nucleation

Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset

EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease

The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease

… this is just a small sample.

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Old 13-10-17, 08:55 AM   #2
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Default Re: Does a higher CAG Repeat Count mean an earlier age of onset?

Good Morning Allan,
I think this thread should be put on a sticky at the beginning.

That is if they still do that.
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