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Frequently asked questions, January 2011

The first in a monthly series of FAQ articles covering hot topics and burning issues in the science behind HD.

What causes Huntington’s disease?

HD (Huntington’s disease) is caused by a mutation in a person’s DNA. Your DNA is basically lots of instructions for building your body and keeping it running. DNA is organized into individual ‘recipes’ called genes. Each gene is a recipe for one protein (a molecular machine). A mutation in a gene is like a spelling mistake. Some spelling mistakes are harmless, but some result in proteins that don’t work properly or are harmful.

The mutation that causes HD was mapped to a specific gene in 1993 – this gene is now called the ‘huntingtin’ gene, and is abbreviated as ‘HTT’ or ‘HD’ or ‘IT15’. Knowing the location and nature of the HD mutation has allowed people to be tested for the HD mutation since 1993.

So what’s all this about ‘CAG’?

Everyone with HD has the same basic type of mutation. It is an expansion of a normal repetitive piece of DNA on chromosome number 4. Chromosomes are long pieces of DNA which are chains of millions of ‘bases’. Each base is like letters of the alphabet spelling a word. Every base is one of 4 chemicals (adenine, cytosine, guanine, thymine). These bases are abbreviated as A, C, G or T.

Near the beginning of everyone’s HD gene is a repetitive stretch of three letters – CAG. In people without HD, these three bases are repeated fewer than 35 times – usually about 17 times. People with 36 or greater repeats of CAG will develop HD if they live long enough.

Traditionally, CAG is pronounced as three separate letters (‘see-ay-gee’) rather than as a word.

How does an expanded CAG repeat cause Huntington’s disease?

Proteins are made from building blocks called amino acids. The three-base sequence CAG in a gene is an instruction to add an amino acid called glutamine to a growing protein. How ever many CAG repeats there are in a huntingtin gene, is how many glutamines will be in the finished protein. So, for example, people with 42 CAG repeats produce a huntingtin protein with 42 glutamine blocks at the start.

Scientists have abbreviations for the different amino acids. Glutamine is abbreviated as ‘Q’, so Huntingtin’s disease is sometimes called a ‘polyglutamine disease’ or a ‘polyQ disease’.

When the huntingtin protein contains too many glutamine blocks, it has a different shape from the normal protein, and behaves differently too. These differences cause the abnormal protein to become harmful to cells, and it’s this harmful behaviour that causes cells to malfunction and die.

Malfunctioning and dying neurons (brain cells), and other cells, are what causes the symptoms of HD.

Can you tell when someone will experience symptoms of HD?

If we look at thousands of HD patients, we find that on average, people with longer CAG-repeat lengths tend to have an earlier age of onset of HD symptoms. At the extreme, people with very long repeats have a severe form of HD with childhood onset. This is often called ‘juvenile HD’ or ‘jHD’. HD patients with adult onset have CAG repeat counts that are lower than juvenile HD patients. The average repeat length in HD patients is about 44.

It’s important to note that the ability to predict age of onset from CAG-repeat length is not at all accurate. Two people with the same CAG repeat length might start to experience symptoms at very different ages – many years or decades different. Because of this, CAG-repeat lengths are useful for scientific and medical research, but aren’t very informative for most people trying to predict their own expected age of onset.

My friend/brother/mom is taking a particular drug for HD – do you think I should?

HDBuzz can’t provide personal medical advice. Any decisions about treatment of HD symptoms should be pursued in consultation with your physician.

Unfortunately, no treatment or drug has ever been shown to delay or prevent symptoms of HD in humans.

However, there are lots of treatments that can help many of the symptoms of HD, and different people may benefit from different treatments. Ask your HD doctor which treatments, if any, might be helpful for you.

What about supplements? Can you tell me which supplements to use, and how much to take?

No. Lots of people with HD do take supplements like creatine, coenzyme Q and many others, but so far, no supplement has been shown to slow down the disease when tested in a randomized, double-blind placebo-controlled trial (the best kind of scientific trial for answering these questions).

This is not to say that these supplements definitely DON’T work, but merely that they haven’t been proven to do so. Until they have, HDBuzz can’t recommend any supplement or treatment.

A number of sites on the net provide advice about supplement use for those who wish to consider taking them – HDAC.org and HDlighthouse.org, for example.

What about alternative treatments for HD?

There are a number of individuals and organizations marketing ‘alternative’ treatments for HD. Many of these like exercise, massage etc. – may be very helpful to many patients.

Other alternative therapies, often marketed as ‘cures’, include shark cell injections, stem cell injections and dietary supplements. There is no evidence that such treatments are effective for slowing down the progression of HD – and they may actually be harmful. We advise that you speak to a doctor experienced in looking after HD patients before considering any treatment.

Of course, if good scientific evidence is produced that any ‘alternative’ treatments are effective, you’ll hear about it from HDBuzz.

It’s worth considering that an ‘alternative medicine’ which has been proven to work automatically becomes ‘medicine’.

Isn’t it true that drug companies don’t care about HD?

We at HDBuzz believe that drug companies have a critical role to play in developing effective therapies for HD patients. They have the experience and ability to run clinical trials that will prove whether drugs are effective.

In the past, it may have been true that drug companies didn’t dedicate many resources to HD. This has changed, and now many drug companies have HD research programs. HDBuzz endorses no individual company or program, and receives no funding from any pharmaceutical company, but we are pleased that both large pharmaceutical companies and small biotechnology companies now have very serious programs and resources dedicated to HD research.

Latest Research Articles

Roche Phase II GENERATION HD2 study underway

Published date: 14 February, 2023

Roche released a community letter last month, detailing how their Phase II clinical trial to study the huntingtin-lowering drug, tominersen, is now underway. Learn more about what this means in this article and at the recent HDSA Research Webinar, with representatives from the company. The ups and downs of huntingtin-lowering Tominersen is a type of ... Read more

Disappointing news from Novartis about branaplam and the VIBRANT-HD trial

Published date: 9 December, 2022

The pharmaceutical company Novartis has released a community update which announces that they are ending development of branaplam, a huntingtin lowering drug, for possible treatment in Huntington’s disease (HD). This news comes following recent bad news about side effects of branaplam in HD patients, being tested in the VIBRANT-HD clinical trial, dosing of which was ... Read more

Update on the PTC Therapeutics PIVOT-HD Trial

Published date: 2 November, 2022

Recruitment of participants into the US arm of the PTC Therapeutics PIVOT-HD trial has been paused. Since this announcement, there have been a lot of different (and confusing!) headlines about the pause in recruitment. In this article, we will lay out what is going on and what this announcement means. What is the aim of ... Read more

Forward momentum for Roche and Wave in latest news about huntingtin-lowering trials

Published date: 30 September, 2022

In the past week or so, during and following a big HD research conference, two companies developing medicines for Huntington’s disease announced news about their huntingtin-lowering drugs. First, the pharmaceutical company Roche announced plans for a new clinical trial of tominersen. Then, the genetic medicines company Wave Life Sciences shared early data showing that its ... Read more

Focusing in on fibrils; scientists give us a glimpse of huntingtin protein clumps

Published date: 8 September, 2022

A group of scientists from the EPFL in Lausanne, Switzerland have published a paper in the Journal of the American Chemical Society, describing clumps made up of a fragment of the huntingtin protein. A word that’s commonly used to describe these is “aggregates.” Using very powerful microscopes, the team was able to zoom in and ... Read more

Hereditary Disease Foundation (HDF) conference 2022 – Day 4

Published date: 2 September, 2022

DNA repair and CAG repeat instability The effect of HTT lowering on CAG repeat expansions Welcome to last day of the @hdfcures conference! We’ll only be sharing a few talks from today’s sessions, which focus on DNA repair. The first is from HDBuzz’s very own Jeff Carroll! Jeff will be sharing his work on HTT ... Read more