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