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Some genetic diseases caused by an abnormal repeat in the DNA are known to become more severe with each new generation - this dreadful trait is called anticipation. Now a study by Portuguese researchers from Porto University has proved for the first time the existence of anticipation in diseases caused by a different type of errors that not a DNA repeat, in this case in the fatal neurodegenerative disorder Familial Amyloid Polyneuropathy (FAP). 

The discovery has two major implications: first it opens the door to the possibility that many more diseases could show anticipation, including Alzheimer’s and cancer, like some already suggested but others dismissed as experimental error. 

Second, and not less important, Carolina Lemos, Alda Sousa and colleagues’ discovery that FAP – a fatal incurable disease - becomes worse from generation to generation might seem bad news, but in fact it has a very positive side. Not only it suggests that if we now can unveil the mechanism how disease becomes worse we might be able to stop it, but also to be able to predict the age of disease onset gives us a transmission pattern that can help patients’ management.

The study in the Journal of Neurology, Neurosurgery and Psychiatry, has already found an effect of gender on FAP onset with men having the disease earlier than women, suggesting a role for sex hormones in the disease and further unveiling this pattern.

So what is FAP?  FAP is a progressive and fatal neurodegenerative (where neurons die) disorder still without a cure or a clear mechanism. We do know, though, that – like in many age-related neurodegenerative disorders including Alzheimer’s and Parkinson’s – the disease is linked to deposits of a mutated protein on neurons, which later die compromising whatever functions they normally control. In FAP case, the mutated protein is a liver protein called Transthyretin (TTR) and the neurons affected belong mostly to the autonomic nervous system, which controls many of our non-conscious visceral functions. As consequence the symptoms that start by a tingling followed by loss of sensation in the lower limbs that spreads to the rest of the body, as the nerve destruction continues eventually reach the autonomic functions crucial to our survival. This means trouble in things like breathing and heart beating that, unless the disease is stopped, result in death in as little as10 years. 

The problem is that so far there is no effective treatment for FAP – until recently this was limited to liver transplants, which not only are difficult to find but imply life-long dangerous medication and can always be rejected.

In 2011, a new drug called Tafamidis (which binds the mutated protein, stopping its aggregation) was made available, but even Tafamidis can only delay the disease’s progression although, if initiated early enough, it can be very efficient arresting the nerve damage even if it cannot cure FAP.

To make things even worse although the disease is rare, when it occurs it can show an incredibly high incidence devastating entire communities. A good example is Póvoa de Varzim and Vila do Conde, two of the most affected areas of Portugal (where FAP was first described) where 1 in every 1000 individuals has the disease, and 1 in every 538 are carriers of the mutated gene 

FAP was initially called  in portuguese "doença dos pezinhos" , literally "feet disease" due to to the fact that its first symptoms occur in the lower limbs 

All this means that the possibility that FAP (or any other neurodegenerative disease) showed anticipation, if true, could represent a potentially important tool to understand the disease and, at the minimum, help patients’ management.

With this aim in mind the teams leaded by Alda Sousa decided to look into the largest database of FAP patients in the world, property of the Hospital de Santo António in Porto, Portugal. 2440 FAP patients from 572 families collected and studied over 70 years, since the disease was first described in the 60s in Portugal. From these, Lemos and colleagues used 926 pairs of parents and children, from 284 different families coming from all over Portugal. And what they discovered was a remarkable pattern of disease transmission.

FAP normally appears in adulthood but when exactly, the researchers discovered, depend much from when the patients’ parents had the disease. For example while most parents with late onset disease (after 50 years of age) had early onset children (around 40 years of age), no early onset parent had late-onset children. Furthermore, the risk of having a very early onset (before 30 years of age) was high for the children of parents with an early onset (around 40 years of age), but null for those with parents developing PAF in their 70s. Finally, the older the parents were when the disease appeared, less probable was that their descendants had early or very early disease. The results were analysed statistically to assure that the differences were real, and the conclusion was that existed a clear pattern of children developing the disease earlier than their parents proving that FAP showed anticipation.

Interestingly Lemos and colleagues also saw that women tended to have later disease than men, whether among parents or children, revealing an effect of gender on FAP onset. This was confirmed by the observation that sons from affected mothers had the larger anticipations (difference between parent-child age of disease onset), while father-daughter pairs showed almost none.

Until now anticipation had only been proved in diseases caused by abnormal repeats of a piece of DNA, which are highly unstable and, as they pass between generations, tend to multiply even more causing an increase in disease severity.  FAP, however, results from a point mutation (which if the TTR gene is seen like a beads necklace, it is a change in a single bead) and yet also shows anticipation. This proves anticipation as a real biological phenomenon, opening the possibility that it might exist in many other disorders.

As Lemos adds “Our results can have some important implications for other diseases caused by point mutations as well, since these mechanisms of anticipation (independent of repeat expansions) are still mysterious.” A potential implication will be for the study of neurodegenerative disorders linked to age, which not only show a similar disease mechanism to FAP (deposits of abnormal proteins killing neurons) but have already been suggested to have anticipation.

For those carrying the TTR mutation, to prove the existence of anticipation and a gender effect reveals a pattern of disease transmission that will allow better counselling, and, most importantly, earlier detection and treatment, a crucial factor for Tafamidis ‘effectiveness. 

Also as Lemos adds “now that we gained more insight into parent-of-origin effects, a strategy to identify genetic modifiers should focus on families, rather than individuals, aiming to unravel the mechanisms of anticipation”

Although what causes anticipation in PAF is still a mystery, there are suspicions that it could result from  several interacting factors in different families, including effects from other genes, epigenetic mechanisms (inherited mechanism that do not involve DNA change, for example an environmental influence) and/or hormonal effects. This last possibility has gained support with the present study showing that the age of disease onset seems to be different for women and men.

So what’s next? “Our current strategies are to search for genetic modifiers, within or closely linked to the TTR gene and to study candidate-genes, associated with TTR pathways that may also be influencing age of onset “ - says Lemos - “We are also looking for epigenetic mechanisms that may explain the observed variability in the different generations.” 

After all, if we can understand why neural death starts earlier, we might be able one day to stop it.

IMAGE: FAP was initially called "feet disease" (doença dos pezinhos in portuguese) because its 1st symptoms are in the lower limbs. It is still called like that in Portugal -  Image by How Soon Ngu

Journal of Neurology, Neurosurgery and Psychiatry 2014 Mar;85(3):326-30. doi: 10.1136/jnnp-2013-305383.Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M. http://jnnp.bmj.com/content/early/2013/09/17/jnnp-2013-305383.full.pdf

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