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Mild-variant A-T

Mild Variant A-T

Although it has been known for some time that in some people with A-T the symptoms appear later and develop more slowly, it is only recently that this has come to be considered as a variant form of A-T. There is not even full agreement over a name for this form of A-T though it is often referred to as Mild-Variant A-T, or Mild A-T. However, this is not a very appropriate name since the symptoms are ultimately the same as for classic A-T and it can only be considered ‘mild’ by comparison.

How many people have mild-variant A-T?

In the United Kingdom, around one in three cases of A-T are mild variant. This is higher than in many parts of the world due to the fact that one specific mutation which gives a milder form of the condition is relatively common in the United Kingdom and Ireland. This mutation, known as IVS40-1050A>G, appears to have originated in the British Isles. It is present in approximately one in seven of all people with A-T.

Because populations vary and other individual populations may have their own genes which are more or less common, it is impossible to say with any accuracy how many people in other countries may have mild-variant A-T. The UK and Ireland are unusual in that the specific mutations have been identified for almost everyone known to have A-T. Nevertheless, if you discount the effect of the IVS40 gene, the UK population would suggest that a good starting estimate for mild variant A-T in other relatively mixed populations would be around 20% or one case in five.

Symptoms

The symptoms of mild-variant A-T, are broadly the same as those of classic A-T, except that they tend to progress more slowly and may also appear later. While some people with this form of A-T are diagnosed in childhood, others receive a diagnosis as adults. For some, the symptoms may have been apparent for a while, perhaps appearing during teenage years, but have been misdiagnosed as another condition. For others, they only reveal themselves in adulthood. This great variety in the ways that individuals experience the condition is typical of A-T.

When the neurological symptoms do develop, they tend to be very similar to those of people with classic A-T. However, they do not usually have significant immunological abnormalities and there is a much lower risk of childhood cancers. Still, this form of A-T is rarer than classic A-T and there is much that we still don’t know about it.

What causes it?

People with A-T have 2 mutations on the ATM gene, one from each parent. Nearly all A-T mutations are ‘truncating mutations’, which means they do not allow the production of any functional ATM protein. However there are a very few mutations that do permit either the production of a small amount of functioning ATM or else the production of a form of ‘mutant ATM’, i.e. incorrectly–produced ATM, which nevertheless does have some effectiveness.

The IVS40 mutation (see above) was identified by Prof Malcolm Taylor and his team at Birmingham University, who have sequenced the genes for nearly all people with A-T in the United Kingdom. This is a so-called ‘leaky splice-site mutation’, which appears to permit around 4% of the normal amount of active ATM to be produced.

There are also a small number of mutations from another category, known as ‘missense mutations’, which create mutant protein which though not correctly built, does have some residual activity. These have also been shown to correspond to people with later and slower onset of the condition.

Diagnosis

If you are diagnosed with A-T in the United Kingdom, diagnosis will be confirmed at Professor Taylor’s laboratory and the specific mutations will be identified (very occasionally there is a problem doing this). Normally, if the individual has a mutation which is known to allow some ATM activity you will be told at the time of diagnosis. However, as is made clear repeatedly in this website, A-T is a condition which varies considerably from individual to individual and it is not possible to draw firm conclusions about how it will progress for any one person.

Living with mild-variant A-T

As with all forms of A-T there is great variation in how individuals are affected. Some may be diagnosed as children, while others may not be diagnosed until well into adult life. The degree and nature of any disabilities along with differences in personal circumstances and character make it impossible to generalise about the impact of A-T on people’s lives.

Those who are diagnosed later have often lived almost unaffected lives up to that point. Some have children and while most will have had them not knowing that they had A-T there is at least one case of a young woman with A-T having a baby in the full knowledge of her condition.